1,2-ethanediol derivative and salt thereof, process for producing the same, and cerebral function-improving agent comprising the same

ABSTRACT

This invention relates to a 1,2-ethanediol derivative and a salt thereof, a process for producing the same, and a cerebral function-improving agent comprising the same. The cerebral function-improving agent of this invention is useful for treating cerebrovascular dementia, senile dementia, Alzheimer&#39;s dementia, sequelae of ischemic encephalopathy and cerebral apoplexy.

This is a Division of application Ser. No. 08/478,810 filed on Jun. 7,1995, now U.S. Pat. No. 5,612,381, which is a Division of applicationSer. No. 08/174,793 filed on Dec. 29, 1993, now U.S. Pat. No. 5,472,984,which is a Division of application Ser. No. 07/940,747 filed on Sep. 8,1992, now U.S. Pat. No. 5,280,032, which is a Continuation ofapplication Ser. No. 07/566,889 filed on Aug. 14, 1990, abandoned, whichis a Continuation-in-Part of application Ser. No. 07/480,114 filed onFeb. 14, 1990, abandoned.

This invention relates to a 1,2-ethanediol derivative and a saltthereof, a process for producing the same, and a cerebralfunction-improving agent comprising the same. The cerebralfunction-improving agent of this invention is useful for treatingcerebrovascular dementia, senile dementia, Alzheimer's dementia,sequelae of ischemic encephalopathy and cerebral apoplexy.

As 1,2-ethanediol derivatives, there are known, for example, thosedescribed in U.S. Pat. No. 2,928,845; J. Pharm. Sci., vol. 50, pp.769-771 (1961); Farmaco. Ed. Sci., vol. 19, pp. 1056-1065 (1964); etc.

These compounds are in use as a local anesthetic. However, nothing isknown as to their use as a cerebral function-improving agent, anantiamnesic agent or a nootropic agent.

WO No. 88/8424 describes that 1,2-ethanediol derivatives can be used forthe remedy of Alzheimer's disease and other degenerative neurologicaldisorders. However, no specific description or example of thesederivatives is given in the application.

Drugs such as cerebral metabolic enhancers, cerebrovasodilators and thelike are currently in use for the remedy of various dementias,particularly dementia of Alzheimer's type and cerebrovascular dementia.

However, no cerebral function-improving agent has been found as yetwhich is useful for treating cerebrovascular dementia, senile dementia,Alzheimer's dementia, sequelae of ischemic encephalopathy and cerebralapoplexy.

An object of this invention is to provide a novel 1,2-ethanediolderivative and a salt thereof.

Another object of this invention is to provide a process for producing anovel 1,2-ethanediol derivative and a salt thereof.

Still another object of this invention is to provide a novel cerebralfunction-improving agent which is useful for treating cerebrovasculardementia, senile dementia, Alzheimer's dementia, sequelae of ischemicencephalopathy and cerebral apoplexy and yet has little side effect.

The present inventors have made study in order to solve theabove-mentioned problems. As a result, it has been found that a1,2-ethanediol derivative represented by the following general formulaI! or a salt thereof has an excellent antiamnesic activity and anexcellent antihypoxic activity and is very useful as a cerebralfunction-improving agent: ##STR1## wherein R¹ represents a substitutedor unsubstituted phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthylor heterocyclic group; R² represents a hydrogen atom, a lower alkylgroup or a hydroxyl-protecting group; R³ represents a hydrogen atom or alower alkyl group; nR⁴ 's and nR⁵ 's are the same as or different fromone another and represent hydrogen atoms or lower alkyl groups; R⁶represents an ammonio group or a substituted or unsubstituted amino ornitrogen-containing heterocyclic group, the nitrogen-containingheterocyclic group being selected from the group consisting of pyrrolyl,pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl,tetrahydropyridyl, pyrimidinyl, morpholinyl, thiomorpholinyl, quinolyl,quinolizinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,quinuclidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl,imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, purinyl andindazolyl groups; and n represents 0 or an integer of 1 to 6; whereinthe substituent on R¹ is selected from the group consisting of halogenatoms, substituted or unsubstituted amino, lower alkyl, aryl, ar-loweralkyl, lower alkoxy, ar-lower alkoxy, aryloxy, carbamoyloxy, loweralkylthio, lower alkenyl, lower alkenyloxy, ar-lower alkylthio, ar-loweralkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylaminoand heterocyclic groups and protected amino groups, protected orunprotected hydroxyl groups, nitro group, oxo group and loweralkylenedioxy groups; the substituted lower alkyl, aryl, ar-lower alkyl,lower alkoxy, ar-lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio,lower alkenyl, lower alkenyloxy, ar-lower alkylthio, ar-loweralkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylaminoor heterocyclic group as the substituent of R¹ and the substitutednitrogen-containing heterocyclic group as R⁶ have each at least onesubstituent selected from the group consisting of halogen atoms,protected or unprotected hydroxyl groups, protected or unprotected aminogroups, protected or unprotected carboxyl groups, unsubstituted loweralkyl groups, lower alkyl groups. substituted by a protected orunprotected hydroxyl group, unsubstituted or halogen-substituted arylgroups, unsubstituted or halogen-substituted aroyl groups, unsubstitutedlower alkoxy groups, lower alkoxy groups substituted by a lower alkoxygroup, lower acyl groups, ar-lower alkyl groups, ar-lower alkenylgroups, heterocyclic groups, heterocyclic-CO-- groups, oxo group, loweralkylsulfonyl groups and arylsulfonyl groups; and the substituted aminogroup as the substituent of R¹ and the substituted amino group as R⁶have each at least one substituent selected from the group consisting ofprotected or unprotected hydroxyl groups, unsubstituted lower alkylgroups, lower alkyl groups substituted by a protected or unprotectedcarboxyl or hydroxyl group, cycloalkyl groups, aryl groups, lower acylgroups, ar-lower alkyl groups, heterocyclic groups, unsubstituted oroxo-substituted heterocyclic-CO-- groups, adamantyl group, loweralkylsulfonyl groups and arylsulfonyl groups, provided that there areexcluded the compounds in which R¹ is a phenyl group which mayoptionally be substituted by the halogen atom or the lower alkyl, loweralkylenedioxy, lower alkoxy or protected or unprotected hydroxyl groupand R⁶ is --NR⁷ R⁸ in which R⁷ represents an ar-lower alkyl orheterocyclic group and R⁸ represents a hydrogen atom or a lower alkylgroup, or R⁷ and R⁸ form, when taken with the N atom, ##STR2## in whichR⁹ represents an aryl or heterocyclic group and i represents 0 or aninteger of 1 to 3, ##STR3## in which R¹⁰ represents an aryl,heterocyclic or ##STR4## group and R⁸ and i have the same meanings asdefined above, ##STR5## in which R¹¹ represents an aryl group, ##STR6##in which R¹² represents a carboxyl group or a lower alkoxycarbonyl groupor ##STR7## in which R¹² has the same meaning as defined above and thecompounds in which R¹ represents an unsubstituted or loweralkyl-substituted phenyl group and R⁶ represents a di-lower alkylaminogroup, ##STR8## all the above heterocyclic groups being selected fromthe group consisting of the nitrogen-containing heterocyclic groupsmentioned in the definition of R⁶ and furyl, thienyl, benzothienyl,pyranyl, isobenzofuranyl, oxazolyl, benzofuranyl, indolyl,benzimidazolyl, benzoxazolyl, benzothiazolyl, quinoxalyl,dihydroquinoxalyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzopyrrolyl,2,3-dihydro-4H-1-thianaphthyl, 2,3-dihydrobenzofuranyl, benzob!dioxanyl, imidazo- 2,3-a!pyridyl, benzo b!piperazinyl, chromenyl,isothiazolyl, isoxazolyl, oxadiazolyl, pyridazinyl, isoindolyl andisoquinolyl groups.

Incidentally, the cerebral function-improving agent mentioned hereinrefers to a cerebral-function-improving agent having not only effectspossessed by conventional cerebral-function-improving agents, forexample, sequelae of ischemic encephalopathy and cerebral apoplexy butalso therapeutic or prophylactic effects for amnesia and dementias (e.g.cerebrovascular dementia, senile dementia and Alzheimer's dementia).

In the present specification, the following terms have the followingdefinitions unless otherwise specified.

The term "halogen atom" means, for example, a fluorine atom, a chlorineatom, a bromine atom and an iodine atom; the term "lower alkyl group"means C₁₋₆ alkyl groups such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, pentyl, hexyl and the like; the term"lower alkoxy group" means C₁₋₆ alkyl-O-- groups; the term "loweralkylthio group" means C₁₋₆ alkyl-S-- groups; the term "lower alkenylgroup" means C₂₋₆ alkenyl groups such as vinyl, propenyl, butenyl,pentenyl, hexenyl and the like; the term "lower alkenyloxy group" meansC₂₋₆ alkenyl-O-- groups; the term "cycloalkyl group" means C₃₋₆cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and the like; the term "aryl group" means phenyl, naphthyl,indanyl and indenyl groups; the term "aryloxy group" means aryl-O--groups; the term "ar-lower alkyl group" means ar-C₁₋₄ alkyl groups suchas benzyl, diphenylmethyl, trityl, phenethyl and the like; the term"ar-lower alkoxy group" means ar-C₁₋₄ alkyl-O-- groups; the term"ar-lower alkylthio group" means aryl-C₁₋₄ alkyl-S-- groups; the term"lower alkylenedioxy group" means C₁₋₄ alkylenedioxy groups such asmethylenedioxy, ethylenedioxy and the like; the term "lower acyl group"means C₁₋₆ acyl groups such as formyl, acetyl, butyryl and the like; theterm "aroyl group" means aryl-CO-- groups; the term "lower alkylsulfonylgroup" means C₁₋₆ alkyl-SO₂ -- groups; the term "arylsulfonyl group"means aryl-SO₂ -- groups; ther term "ar-lower alkylsulfonyl group" meansaryl-C₁₋₆ alkyl-SO₂ -- groups; the term "lower alkylsulfonyloxy group"means C₁₋₆ alkyl-SO₂ --O-- groups; the term "arylsulfonyloxy group"means aryl-SO₂ --O-- groups; the term "lower alkylsulfonylamino group"means C₁₋₆ alkyl-SO₂ --NH-- groups; the term "arylsulfonylamino group"means aryl-SO₂ NH-- groups; the term "di-lower alkylamino group" meansdi-C₁₋₆ alkyl-NH-- groups and the term "ammonio group" means tri-loweralkylammonio groups such as trimethylammonio, triethylammonio; the term"lower alkoxycarbonyl group" means C₁₋₆ alkyl-O--CO-- groups and thelike.

The protective groups for hydroxyl group, carboxyl group and amino groupinclude those conventional protective groups for hydroxyl group,carboxyl group and amino group which are described in Protective Groupsin Organic Synthesis Theodra W. Green (1981), John Wiley & Sons, Inc.!.In particular, the protective group for hydroxyl group specificallyincludes, for example, lower alkyl, lower acyl, tetrahydropyranyl andar-lower alkyl groups such as substituted or unsubstituted benzyl.

The salt of the 1,2-ethanediol derivative represented by the generalformula I! can be any pharmaceutically acceptable salt. It includes, forexample, salts with mineral acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid and the like; salts with carboxylicacids such as formic acid, acetic acid, oxalic acid, fumaric acid,maleic acid, malic acid, tartaric acid, aspartic acid and the like;salts with sulfonic acids such as methanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like; andsalts with alkali metals such as sodium, potassium and the like.

When the 1,2-ethanediol derivative of the general formula I! or its salthas isomers (e.g. optical isomers, geometrical isomers, tautomers), allof these isomers are included in this invention. Also, the hydrate,solvate and all crystal forms of the compound of this invention areincluded in this invention.

Next, there is described a process for producing a 1,2-ethanediolderivative of the general formula I! or a salt thereof.

The 1,2-ethanediol derivative of the general formula I! or its salt canbe produced by per se known processes or their appropriate combinations,for example, the following production processes. ##STR9##

In the above reaction schemes, R¹, R², R³, R⁴, R⁵, R⁶ and n have thesame meanings as defined above; R^(2a) represents the samehydroxyl-protecting group as in the definition of R² ; R^(6a) representsthe same substituted or unsubstituted nitrogen-containing heterocyclicgroup as in the definition of R⁶, provided that the heterocyclic grouphas a free valence on a carbon atom forming the heterocyclic ring;R^(6b) represents the same substituted or unsubstitutednitrogen-containing heterocyclic group as in the definition of R⁶,provided that the nitrogen-containing heterocyclic group has a freevalence on a nitrogen atom forming the heterocyclic ring, or asubstituted or unsubstituted amino group; R¹³ represents the samehydroxyl-protecting group as in the definition of R² ; X¹ and X², whichmay be the same or different, represent halogen atoms, Y represents aremovable group such as a halogen atom, a lower alkylsulfonyloxy group,an arylsulfonyloxy group or the like; Y^(a) represents anarylsulfonyloxy group; and m represents an integer of 1-6.

As the salts of the compounds of the general formulas III!, IIIa!, IV!,V!, VII!, IX!, X!, XI!, XII!, XVI!, Ia!, Ib!, Ic! and Id!, there can bementioned the same salts as the salts of the compound of the generalformula I!.

Next, each of the above production processes is described.

Production Process 1

A compound of the general formula II! is reacted with a compound of thegeneral formula III! or its salt or a compound of the general formulaIIIa! or its salt in the presence or absence of a base to obtain acompound of the general formula Ia! or its salt.

The solvent to be used in this reaction can be any solvent unless itadversely affects the reaction. There can be mentioned, for example,aromatic hydrocarbons such as benzene, toluene, xylene and the like;sulfoxides such as dimethylsulfoxide and the like; amides such asN,N-dimethylformamide and the like; and ethers such as tetrahydrofuran,dioxane and the like. These solvents can be used alone or in admixtureof two or more. It is also possible to use the compound of the generalformula III! or IIIa! as the solvent.

As the base to be used optionally, there can be mentioned, for example,sodium hydride, metallic sodium and potassium tert-butoxide.

In the reaction, the compound of the general formula III! or its salt,or the compound of the general formula IIIa! or its salt is used in anamount of 1-100 moles, preferably 1-10 moles, per mole of the compoundof the general formula II!.

The base as an optional component is used in an amount of 0.01-1.2 molesper mole of the compound of the general formula II!.

This reaction can be effected usually at 20°-150° C., preferably 70°-90°C., for 1 minutes to 24 hours, preferably 5 minutes to 5 hours.

Production Process 2

(1) A compound of the general formula II! is reacted with a compound ofthe general formula IV! or its salt in the presence or absence of a baseto obtain a compound of the general formula V! or its salt.

This reaction can be effected in the same manner as described inProduction Process 1.

The obtained compound of the general formula V! or its salt may be usedin the subsequent reaction without being isolated.

(2) The compound of the general formula V! or its salt is subjected toconventional reaction for protection of hydroxyl group to obtain acompound of the general formula VI!.

The obtained compound of the general formula VI! may be used in thesubsequent reaction without being isolated.

Then, the compound of the general formula VI! is subjected to reactionfor selective removal of the hydroxyl-protecting group to obtain acompound of the general formula VII! or its salt.

The obtained compound of the general formula VII! or its salt may beused in the subsequent reaction without being isolated.

These reactions can be effected according to per se known methods, forexample, the method described in Protective Groups in Organic SynthesisTheodra W. Green (1981), John Wiley & Sons, Inc.! or a method similarthereto.

The combination of the hydroxyl-protecting groups (R¹³ and R^(2a)) to beused in these reactions can be selected appropriately.

(3) The compound of the general formula VII! or its salt is reacted witha halogenating agent or a sulfonylating agent in a solvent in thepresence or absence of a base to obtain a compound of the generalformula VIII!.

The solvent to be used in the reaction can be any solvent unless itadversely affects the reaction. There can be mentioned, for example,halogenated hydrocarbons such as methylene chloride, chloroform and thelike; ethers such as tetrahydrofuran, dioxane and the like; nitrilessuch as acetonitrile and the like; and amides such asN,N-dimethytformamide and the like. These solvents can be used alone orin admixture of two or more.

As the base to be used optionally, there can be mentioned, for example,organic and inorganic bases such as triethylamine,diisopropylethytamine, 1,8-diazabicyclo- 5.4.0!undec-7-ene (DBU),pyridine, potassium tert-butoxide, sodium carbonate, potassiumcarbonate, sodium hydride and the like.

As the halogenating agent, there can be mentioned, for example,phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride,phosphorus pentachloride, thionyl chloride and the like.

As the sulfonylating agent, there can be mentioned, for example,methanesulfonyl chloride, p-toluenesulfonyt chloride and the like.

Each of the halogenating agent, the sulfonylating agent and the base asan optional component is used in an amount of at least 1 mole,preferably 1-2 moles, per mole of the compound of the general formulaVII! or its salt.

This reaction can be effected usually at -10° to 100° C., preferably 0°to 40° C., for 10 minutes to 30 hours.

The obtained compound of the general formula VIII! may be used as it is,in the subsequent reaction without being isolated.

(4) The compound of the general formula VIII! is reacted with a compoundof the general formula IX! or its salt in the presence or absence of acatalyst in the presence or absence of a base to obtain a compound ofthe general formula Ib! or its salt.

The solvent to be used in this reaction can be any solvent unless itadversely affects the reaction. There can be mentioned, for example, thesame solvents as mentioned in (3) of Production Process 2.

As the catalyst to be used optionally, there can be mentioned, forexample, potassium iodide, sodium iodide and the like.

The catalyst is used in an amount of 0.1-1 mole per mole of the compoundof the general formula VIII!.

As the base to be used optionally, there can be mentioned, for example,the same bases as mentioned in (3) of Production Process 2.

Each of the compound of the general formula IX! or its salt and the baseas an optional component is used in an amount of at least 1 mole,preferably 1-20 moles, per mole of the compound of the general formulaVIII!.

This reaction can be effected usually at 10°-150° C., preferably20°-100° C. for 10 minutes to 20 hours.

Production Process 3

(1) A compound of the general formula II! is reacted with a compound ofthe general formula X! or its salt in the presence or absence of a baseto obtain a compound of the general formula XI! or its salt.

This reaction can be effected in accordance with the same method asmentioned in Production Process 1.

(2) The compound of the general formula XI! or its salt is reacted witha sulfonylating agent in a solvent in the presence or absence of a baseto obtain a compound of the general formula XII! or its salt.

The solvent to be used in this reaction can be any solvent unless itadversely affects the reaction. There can be mentioned, for example, thesame solvents as mentioned in (3) of Production Process 2.

As the base to be used optionally, there can be mentioned, for example,the same bases as mentioned in (3) of Production Process 2.

As the sulfonylating agent, there can be mentioned, for example,p-toluenesulfonyl chloride and the like.

Each of the sulfonylating agent and the base as an optional component isused in an amount of at least 0.95 mole, preferably 1-2 moles, per moleof the compound of the general formula XI! or its salt.

This reaction can be effected usually at -10° to 100° C., preferably 0°to 40° C., for 10 minutes to 30 hours.

The obtained compound of the general formula XII! or its salt may beused in the subsequent reaction without being isolated.

(3) The compound of the general formula XII! or its salt is subjected toconventional reaction for protection of hydroxyl group to obtain acompound of the general formula XIII!.

The reaction can be effected in accordance with per se known methods,for example, the method described in Protective Groups in OrganicSynthesis Theodra W. Green (1981), John Wiley & Sons, Inc.! or a methodsimilar thereto.

The obtained compound of the general formula XIII! may be used in thesubsequent reaction without being isolated.

(4) The compound of the general formula XII! or its salt or the compoundof the general formula XIII! is reacted with a compound of the generalformula IX! or its salt in the presence or absence of a base to obtain acompound of the general formula Ic! or its salt.

as described in (4) of Production Process 2.

Production Process 4

(1) A compound of the general formula XIV! is reacted with a compound ofthe general formula XV! to obtain a compound of the general formula XVI!or its salt.

The solvent to be used in this reaction can be any solvent unless itadversely affects the reaction. There can be mentioned, for example,ethers such as diethyl ether, tetrahydrofuran, dioxane and the like; andaromatic hydrocarbons such as benzene, toluene and the like. Thesesolvents can be used alone or in admixture of two or more.

In this reaction, the compound of the general formula XV! is used in anamount of 0.8-100 moles, preferably 0.8-10 moles, per mole of thecompound of the general formula XIV!.

This reaction can be effected usually at -78° to 100° C., preferably-78° to 50° C. for 5 minutes to 24 hours.

The obtained compound of the general formula XVI! or its salt may beused in the subsequent reaction without being isolated.

Incidentally, the compound of the general formula XV! to be used in thisreaction can be produced according to a per se known method, forexample, the method described in Bull. Soc. Chim. Fr., 1967 (5), pp.1533-40.

(2) The compound of the general formula XVI! or its salt is reacted witha compound of the general formula IX! or its salt in the presence orabsence of a base to obtain a compound of the general formula Id! or itssalt.

The solvent to be used in this reaction can be any solvent unless itadversely affects the reaction. There can be mentioned, for example,halogenated hydrocarbons such as methylene chloride, chloroform and thelike; ethers such as tetrahydrofuran, dioxane and the like; alcoholssuch as ethanol, propanol, butanol and the like; nitriles such asacetonitrile and the like; and amides such as N,N-dimethylformamide andthe like. These solvents can be used alone or in admixture of two ormore.

As the base to be used optionally, there can be mentioned, for example,the same bases as mentioned in (3) of Production Process 2.

Each of the compound of the general formula IX! or its salt and the baseas an optional component is used in an amount of at least 1 mole,preferably 1-20 moles, per mole of the compound of the general formulaXVI! or its salt.

This reaction can be effected usually at 10°-150° C., preferably20°-100° C., for 10 minutes to 20 hours.

In the above production processes, the reactants or base can also beused as solvent depending on the nature of the reactants or base.

In the above production processes, when the compounds of the generalformulas II!, III!, IIIa!, IV!, IV!, VI!, VII!, VIII!, IX!, X!, XI!,XII!, XIII!, XIV!, XV! and XVI!, have isomers (e.g. optical isomers,geometrical isomers, tautomers), the compounds can be used in any isomerform. Further, the compounds can be used in a hydrate form, a solvateform or any crystal form.

When the compounds of the general formulas II!, III!, IIIa!, IV!, V!,VI!, VII!, VIII!, IX!, XII!, XIII!, XIV!, XV!, XVI!, I!, Ia!, Ib!, Ic!and Id! have a hydroxyl group, an amino group or a carboxyl group, it ispossible to previously protect these groups with a conventionalprotective group and to remove, after the reaction, the protectivegroup, if necessary, according to a per se known method.

The compound thus obtained may be subjected to conventional isolationand purification procedures such as column chromatography,crystallization, distillation, extraction and the like.

The 1,2-ethanediol derivative of the general formula I! or its salt canbe converted into other 1,2-ethanediol derivative of the general formulaI! or its salt by subjecting the former compound to appropriatecombination of per se known reactions such as oxidation reaction,reduction reaction, addition reaction, acylation reaction, alkylationreaction, sulfonylation reaction, deacylation reaction, substitutionreaction, dehydration reaction, hydrolysis reaction and the like.

The compound of the general formula II! which is the starting materialfor producing the compound of this invention can be produced by per seknown processes, for example, the process described in JACS, vol. 87, p.1353 (1965) and the process described in Shin Jikken Kagaku Koza, vol.14, p. 579 (1977), Maruzen.

The compound of this invention, when used as a drug, may beappropriately mixed with excipients such as filler, carrier, diluent andthe like and can be formed into tablets, capsules, powders, granules,fine granules, pills, suspensions, emulsions, liquids, syrups,injections, etc. according to conventional methods. These drugs can beadministered orally or parenterally. The dosage route, dose and numberof administrations can be appropriately varied depending upon the age,weight and symptom of patient, but in the case of oral administration,generally 0.01-500 mg of the present compound can be administered dailyto an adult patient in one to several portions.

Next, the pharmacological activities of representative compounds of thisinvention are described.

The numbers of the test compounds used in the following pharmacologicaltests refer to the numbers of the compounds shown in Production Examplesappearing hereinafter.

1. Effect of test compound on hypoxia

A test compound dissolved in physiological saline (100 mg/kg) was orallyadministered to a ddY female mouse (5-6 weeks old, each group consistingof 10 mice). After 1 (or 30 minutes*) hour from the administration, eachmouse was placed in a 300-ml glass chamber, and a gas mixture consistingof 4% of oxygen and 96% of nitrogen was passed through the chamber at arate of 5 liters/min. A time from the start of gas passing to the deathof each mouse was measured.

To a control mice group was orally administered only physiologicalsaline.

The antihypoxic activity of the test compound was calculated from thefollowing formula: ##EQU1##

The results are shown in Table 1.

                  TABLE 1                                                         ______________________________________                                                  Antihypoxic           Antihypoxic                                   Compound  activity    Compound  activity                                      No.       (%)         No.       (%)                                           ______________________________________                                        1         155          48       160                                           2         119          49       151                                           3         245*         54       137                                           9         113          55       207                                           14        184*         56       182                                           15        194*         58       133                                           16        116          61       184*                                          19        168*         62       127                                           23        241*         67       247*                                          27        201*         71       147                                           33        224*         83       177*                                          34        221          84       175*                                          36        139          86       130*                                          37        148          87       179                                           42        194          89       156*                                          46        150*         92       169                                           47        165*         95       164                                           96        176*        204       176*                                          97        138*        207       136*                                          98        164*        208       242*                                          100       171*        209       148*                                          102       140*        211       177*                                          104       160*        213       149                                           119       175*        215       197                                           120       162*        218       157*                                          121       149*        219       222*                                          122       142*        220       183*                                          123       140*        221       183*                                          125       172*        222       152*                                          126       172*        223       149*                                          129       158*        224       155                                           131       167*        225       157*                                          132       133*        228       144                                           134       201*        229       123                                           137       163*        230       177                                           139       162*        231       246                                           151       182         232       150                                           152       180         236       177                                           153       185         237       149                                           167       165         238       123                                           180       176*        239       150                                           181       132         243       159                                           187       153*        246       128                                           188       144*        247       124                                           195       176*        250       145*                                          197       164*        251       186*                                          203       177*        252       190*                                          256       154         342       157*                                          259       155*        343       160*                                          260       124         344       268*                                          261       126         345       185*                                          271       150*        347       162*                                          272       185*        348       251*                                          279       198         349       209*                                          282       160*        350       147*                                          283       183         353       132*                                          289       157*        357       189*                                          302       182*        358       211*                                          303       168         365       155*                                          309       198*        368       135*                                          312       221*        369       143*                                          313       154*        375       156*                                          320       212*        377       221*                                          325       217*        383       293*                                          327       160*        385       161*                                          330       242*        286       169*                                          332       230*        387       228*                                          334       246*        388       213*                                          336       224*        390       248*                                          337       309*        394       241*                                          338       144*        396       316*                                          339       131*        398       171*                                          340       163*        405       137*                                          410       153*        419        185**                                        411       167*        421       274*                                          413       157*        422       256*                                          414       172*        423       279*                                          415       129*        428       274*                                          418        191**      429       251*                                          ______________________________________                                         Note:                                                                         *Mice were placed in the chamber after 30 minutes from the administration     instead of after 1 hr from the administration.                                **25 mg/kg of the test compound was administered to mice instead of 100       mg/kg of the test compound, and mice were placed in the chamber after 30      minutes from the administration instead of after 1 hour from the              administration.                                                          

2. Effect of test compound on amnesia

(1) Electroconvulsive shock (ECS)-induced amnesia

A test compound dissolved in physiological saline was intraperitoneallyadministered to a ddY male mouse (5-6 weeks old, each group consistingof 10 mice). The acquisition trial in passive avoidance task was carriedout after 1 hour from the administration. Each mouse was placed in thebright compartment of a two-compartment step-through type passiveavoidance apparatus consisting of a bright compartment and a darkcompartment (MPA-100M manufactured by Muromachi Kikai). When the mouseentered the dark compartment, the guilotine door of the dark compartmentwas closed; after 0.5 second, an inescapable footshock (1.6 mA, 3seconds) was delivered immediately thereafter, ECS (25 mA, 0.5 second)was applied through the both eyes of the mouse. After 24 hours, in theretention trial, the mouse was again placed in the bright compartmentand the response latency for mouse to enter the dark compartment wasmeasured. If the mouse avoided longer than 300 seconds, a ceiling scoreof 300 seconds was assigned.

A control mice group to which only physiological saline had beenadministered intraperitoneally, and response latency was also measuredin the same manner.

Antiamnesic activity was taken as a median of the response latencies ofthe 10 mice and expressed by the following symbols:

-: 0-60 seconds

+: 61-100 seconds

++: 101-150 seconds

+++: 151-300 seconds

The results are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Compound       Dosage   Antiamnesic                                           No.            (mg/Kg)  activity                                              ______________________________________                                        2              3        +                                                     3              3        +++                                                   8              3        +                                                     15             3        +++                                                   19             3        +                                                     23             10       +                                                     29             3        +                                                     44             10       ++                                                    48             3        ++                                                    52             3        +                                                     53             3        +++                                                   58             10       ++                                                    61             3        ++                                                    67             3        ++                                                    70             3        ++                                                    76             3        ++                                                    78             3        ++                                                    115            3        ++                                                    159            3        +                                                     160            3        ++                                                    170            3        ++                                                    176            3        ++                                                    189            3        +++                                                   228            10       +                                                     229            3        +                                                     235            10       ++                                                    237            3        ++                                                    239            10       +                                                     243            3        ++                                                    252            3        +++                                                   261            3        +                                                     266            3        ++                                                    315            3        ++                                                    316            3        +                                                     319            10       ++                                                    ______________________________________                                    

(2) Effect of test compound on cycloheximide-induced amnesia

It was reported by Yamazaki et al. Drugs, Mind and Action, vol. 3, pp.127-136 (1983)! that cycloheximide interfers with the retrieval processof memory of mouse. Hence, the following test was carried out.

A test was carried out in accordance with the method described in Drugs,Mind and Action, vol. 3, pp. 127-136 (1983) and Folia PharmacologicaJaponica, vol. 89, pp. 243-252 (1987).

As the test apparatus, there was used a step-down type passive avoidancetraining box. It was a black acrylic resin box of 22 cm×22 cm×21 cm(height) whose floor portion consisted of a stainless steel grid andwhich had, at one corner of the floor grid, a platform of 7 cm×7 cm×2 cm(height).

Cycloheximide was dissolved in physiological saline, and injectedsubcutaneously at 120 mg/kg to a ddY male mouse (5-6 weeks old, eachgroup consisting of 10 mice). In an acquisition trial, after 15 minutesfrom the administration, each mouse was placed on the platform in theabove test apparatus. As soon as the mouse stepped down the platform, a2 mA current was delivered for 2 seconds, immediately after which themouse was returned to its home cage. A retention test was performed 24hours after the acquisition. To each mouse which had been treated withcycloheximide was orally administered a test compound dissolved inphysiological saline; after 30 minutes from the administration, themouse was again placed on the platform and the response latency formouse to step down was measured. If the mouse avoided longer than 300seconds, a ceiling score of 300 seconds was assigned.

A control mice group to which only physiological saline had beenadministered orally, and response latency was also measured in the samemanner.

Antiamnesic activity was taken as a median of the response latencies ofthe 10 mice and expressed by the following symbols:

-: 0-60 seconds

+: 61-100 seconds

++: 101-150 seconds

+++: 151-300 seconds

The results are shown in Table 3.

                  TABLE 3                                                         ______________________________________                                        Compound       Dosage   Antiamnesic                                           No.            (mg/Kg)  activity                                              ______________________________________                                        1              3        ++                                                    7              10       +                                                     9              10       +                                                     14             3        +++                                                   15             3        +++                                                   16             10       +                                                     25             3        +                                                     28             10       +                                                     42             3        +                                                     48             3        ++                                                    49             3        ++                                                    54             3        ++                                                    56             3        +                                                     60             3        +++                                                   65             3        ++                                                    82             3        ++                                                    83             3        +                                                     84             10       ++                                                    100            3        ++                                                    110            10       ++                                                    112            3        +++                                                   113            3        ++                                                    115            3        +++                                                   147            3        +++                                                   151            3        +++                                                   153            3        ++                                                    165            10       +                                                     178            3        +++                                                   181            10       ++                                                    194            3        +                                                     196            3        +++                                                   219            3        +                                                     220            10       ++                                                    221            10       +                                                     228            3        ++                                                    229            10       ++                                                    230            3        +                                                     232            10       ++                                                    233            3        +                                                     234            3        +                                                     235            3        +++                                                   238            3        +                                                     240            3        +                                                     241            3        ++                                                    242            3        ++                                                    244            3        ++                                                    245            10       ++                                                    246            3        ++                                                    248            3        ++                                                    251            3        +++                                                   252            30       +++                                                   257            3        +                                                     260            3        +                                                     261            3        +++                                                   262            3        +                                                     263            10       +                                                     266            30       +                                                     280            10       +                                                     312            10       +                                                     317            3        ++                                                    320            3        ++                                                    324            10       ++                                                    325            10       ++                                                    333            3        +                                                     334            3        +                                                     338            3        ++                                                    339            10       +                                                     340            3        +                                                     341            3        +                                                     343            10       ++                                                    346            3        +                                                     350            3        ++                                                    351            3        +                                                     352            3        ++                                                    353            3        +                                                     358            10       ++                                                    360            10       +                                                     365            3        +                                                     367            3        +++                                                   368            3        +                                                     Control        --       --                                                    ______________________________________                                    

3. Inhibitory activity for acetylcholinesterase

A test was conducted in accordance with the method of Ellman et al.Biochem. Pharmacol., vol. 7, pp. 88-95, 1961!.

That is, acetylthiocholine (as a substrate) was added to a phosphatebuffer solution containing 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB),a test compound and a mouse cerebral homogenate (as anacetylcholinesterase source). The resulting mixture was incubated, andthe amount of the resulting 5-thio-2-nitrobenzoic acid wasphotometrically measured at 412 nm.

The inhibitory activity for acetylcholinesterase of the test compoundwas expressed by the inhibition (%) when the final concentration of thetest compound was 10 g/ml.

The results are shown in Table 4.

                  TABLE 4                                                         ______________________________________                                        Compound  Inhibition  Compound  Inhibition                                    No.       (%)         No.       (%)                                           ______________________________________                                        6         13          78        90                                            30        22          83        93                                            34        26          86        50                                            37        45          89        44                                            38        36          90        52                                            40        26          97        38                                            47        38          103       36                                            48        51          113       45                                            54        83          165       24                                            55        22          182       38                                            58        45          190       76                                            60        71          222       83                                            61        89          223       74                                            62        78          224       36                                            65        62          225       43                                            67        90          228       30                                            70        91          230       25                                            71        87          233       59                                            72        92          237       44                                            73        89          239       22                                            241       31          341       61                                            246       30          342       67                                            247       26          350       42                                            260       43          352       26                                            302       38          372       30                                            319       30          377       23                                            322       20          386       47                                            329       45          405       59                                            336       21                                                                  ______________________________________                                    

4. Acute toxicity

A test compound dissolved in physiological saline was intravenouslyadministered to a group of ddY male mice (5-6 weeks old) to examine theacute toxicity of the test compound.

As a result, test compound Nos. 1, 2, 3, 6, 8, 9, 15, 16, 25, 30, 33,34, 38, 40, 42, 44, 46, 52, 53, 54, 65, 67, 70, 71, 112, 119, 120, 126,132, 147, 151, 159, 160, 170, 176, 178, 182, 190, 194, 209, 219, 220,221, 229, 235, 236, 240, 251, 256, 279, 283, 309, 312, 313, 315, 316,319, 325, 327, 337, 360, 368, 369, 375, 377, 385, 390 and 396 gave nodeath case at 50 mg/kg.

It is easily appreciated from the above test results that the compoundof this invention is excellent in antihypoxic activity, antiamnesicactivity and inhibitory activity for acetylcholinesterase and has lowtoxicity.

From the above result, it is also easily appreciated that the cerebralfunction-improving agent of this invention is useful for treatingcerebrovascular dementia, senile dementia, Alzheimer's dementia,sequelae of ischemic encephalopathy and cerebral apoplexy.

Next, the process for producing the compound of this invention isspecifically described by way of Production Examples.

In the Production Examples, the mixing ratio of eluant is by volume inall cases and, as the carrier in column chromatography, there was used asilica gel (Kieselgel 60, Art. 7734) manufactured by Merck Co.

The abbreviations used in the Production Examples have the followingmeanings.

Me: methyl, Et: ethyl, i-Pr: isopropyl, t-Bu: tert-butyl, Ac: acetyl,Ph: phenyl, DPM: diphenylmethyl, Bz: benzyl, Tr: trityl, IPA: isopropylalcohol, IPE: diisopropyl ether, PTS: p-toluenesulfonic acid.

In the following sentences and tables, the substances in ! refer tosolvents used in recrystallization.

Production Example 1

(1) A mixture of 10.8 g of (L)-dibenzoylcystine, 1.6 g of lithiumborohydride, 2.4 g of tert-butanol and 180 ml of tetrahydrofuran wasrefluxed for 1 hour and then cooled to -60° C. Thereto was added 6.1 gof 4-benzyloxyphenacyl bromide. The mixture was stirred for 30 minutesat the same temperature and further for 3 hours at -40° to -30° C. Thereaction mixture was added to a mixture of 100 ml of water and 200 ml ofdiethyl ether. The organic layer was separated, washed with water, asaturated aqueous sodium hydrogencarbonate solution and a saturatedaqueous sodium chloride solution in this order, and dried over anhydrousmagnesium sulfate. The solvent was removed by distillation under reducedpressure. The residue thus obtained was purified by columnchromatography (eluant: toluene) to obtain 2.8 g of(S)-1-(4-benzyloxyphenyl)-2-bromoethanol.

(2) 2.8 g of (S)-1-(4-benzyloxyphenyl)-2-bromoethanol was dissolved in amixed solvent of 20 ml of methanol and 10 ml of tetrahydrofuran. To thesolution was added a solution of 0.8 g of potassium hydroxide dissolvedin 4 ml of water, with ice cooling. The mixture was stirred for 5minutes at the same temperature and further for 10 minutes at roomtemperature. The reaction mixture was added to a mixture of 50 ml ofdiethyl ether and 50 ml of ice water. The organic layer was separated.The aqueous layer was extracted with 25 ml of diethyl ether. The extractwas combined with the previously separated organic layer. The combinedorganic layer was washed with water and a saturated aqueous sodiumchloride solution in this order, and dried over anhydrous magnesiumsulfate. The solvent was removed by distillation under reduced pressureto obtain 1.4 g of (S)-2-(4-benzyloxyphenyl)oxirane.

Melting point: 56°-61° C.

Optical rotation: α!_(D) ²⁵ =+5.2° (C=2, CHCl₃)

The following compounds were obtained in the same manner.

o(S)-2-(3-Methylphenyl) oxirane

α!_(D) ²⁵ =+15.7° (C=2, CHCl₃)

o(S)-2-(4-Phenoxyphenyl)oxirane

α!_(D) ²⁵ =+12.5° (C=4, CHCl₃)

Production Example 2

(1) A solution of 23 g of (+)-diisopinocamphenylchloroborane dissolvedin 30 ml of tetrahydrofuran was cooled to -25° C. Thereto was added 12 gof 4-benzyloxyphenacyl bromide. The resulting mixture was stirred for 4hours at -20° to -15° C. The reaction mixture was added to a mixture of150 ml of diethyl ether and 100 ml of ice water. The organic layer wasseparated, washed with water and a saturated aqueous sodium chloridesolution in this order, and dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation under reduced pressure. The residuethus obtained was purified by column chromatography (eluant:hexane:toluene=1:2) to obtain 6.8 g of(R)-1-(4-benzyloxyphenyl)-2-bromoethanol.

(2) 6.0 g of (R)-1-(4-benzyloxyphenyl)-2-bromoethanol was dissolved in amixed solvent of 50 ml of methanol and 25 ml of tetrahydrofuran. Theretowas added a solution of 1.5 g of potassium hydroxide dissolved in 5 mlof water, with ice cooling. The resulting mixture was stirred for 5minutes at the same temperature and further for 10 minutes at roomtemperature. The reaction mixture was added to a mixture of 100 ml ofdiethyl ether and 100 ml of ice water. The organic layer was separated.The aqueous layer was extracted with 50 ml of diethyl ether. The extractwas combined with the previously separated organic layer. The combinedorganic layer was washed with water and a saturated aqueous sodiumchloride solution in this order, and dried over anhydrous magnesiumsulfate. The solvent was removed by distillation under reduced pressureto obtain 3.7 g of (R)-2-(4-benzyloxyphenyl)oxirane.

Melting point: 58°-67° C.

Optical rotation: α!_(D) ²⁶ =-14.4° (C=2, CHCl₃)

The following compounds were obtained in the same manner.

o(R)-2-(3-Methylphenyl)oxirane

α!_(D) ²⁷ =-18.6° (C=2, CHCl₃)

o(R)-2-(4-Phenoxyphenyl)oxirane

α!_(D) ²⁵ =-11.3° (C=2, CHCl₃)

(3) A solution of 7.5 g of (+)-diisopinocamphenylchloroborane dissolvedin 15 ml of tetrahydrofuran was cooled to -25° C. Thereto was added 4 gof 5-bromoacetylbenzo b!thiophene. The resulting mixture was stirred for4 hours at -20° C. to -15° C. The reaction mixture was added to amixture of 80 ml of ethyl acetate and 80 ml of ice water. The organiclayer was separated, washed with water and a saturated aqueous sodiumchloride solution in this order, and dried over anhydrous magnesiumsulfate. The solvent was removed by distillation under reduced pressure.The residue thus obtained was purified by column chromatography (eluant:hexane:ethyl acetate=10:1) to obtain 3.8 g of (R)-1-(benzob!thiophen-5-yl)-2-bromoethanol.

(4) 3.5 g of (R)-1-(benzo b!thiophen-5-yl)-2-bromoethanol was dissolvedin a mixed solvent of 20 ml of methanol and 10 ml of tetrahydrofuran.Thereto was added a solution of 1.5 g of potassium hydroxide dissolvedin 5 ml of water, with ice cooling. The resulting mixture was stirredfor 5 minutes at the same temperature and further for 10 minutes at roomtemperature. The reaction mixture was added to a mixture of 60 ml ofdiethyl ether and 60 ml of ice water. The organic layer was separated.The aqueous layer was extracted with 30 ml of diethyl ether. The extractwas combined with the previously separated organic layer. The combinedorganic layer was washed with water and a saturated aqueous sodiumchloride solution in this order, and dried over anhydrous magnesiumsulfate. The solvent was removed by distillation under reduced pressureto obtain 1.9 g of (R)-2-(benzo b!thiophen-5-yl)oxirane.

Melting point: 72°-76° C.

Optical rotation: α!_(D) =-8.4° (C=2, CHCl₃)

The following compounds were obtained in the same manner.

O(S)-2-(benzo b!thiophen-5-yl)oxirane.

Melting point: 72°-75° C.

α!_(D) =+8.8° (C=2, CHCl₃).

Production Example 3

3.4 g of potassium tert-butoxide was added to 31 ml of2-(N,N-dimethylamino)ethanol. The resulting mixture was heated to 80° C.Thereto was dropwise added 7.7 g of 2-(3-fluorophenyl)oxirane over 40minutes. The mixture was stirred for 3 hours at the same temperature.The reaction mixture was added to a mixture of 200 ml of ice water and200 ml of ethyl acetate. The organic layer was separated. To the organiclayer was added 50 ml of water. The mixture was adjusted to pH 1 with 6Nhydrochloric acid. The aqueous layer was separated and mixed with 100 mlof chloroform. The resulting mixture was adjusted to pH 11 with a 2Naqueous sodium hydroxide solution. The organic layer was separated,washed with water, and dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation under reduced pressure. The residuethus obtained was purified by column chromatography (eluant:chloroform/ethanol=5/1). The resulting oily product was dissolved in 25ml of acetone. Hydrogen chloride gas was blown into the solution. Theresulting crystals were collected by filtration, washed with acetone anddried to obtain 3.1 g of 2-2-(N,N-dimethylamino)ethoxy!-1-(3-fluorophenyl)ethanol hydrochloride(compound No. 1).

Melting point: 164°-165° C. EtOH!

The compounds shown in Table 5 were obtained in the same manner.

In Table 5, R¹, R², R³, R^(4a), R^(4b), R⁶, na and nb each show asubstituent or integer used in the following formula.

                                      TABLE 5                                     __________________________________________________________________________     ##STR10##                                                                    Compound                                          Addition                                                                           Melting                No.   R.sup.1              R.sup.2                                                                         R.sup.3                                                                         R.sup.4a                                                                        R.sup.4b                                                                         R.sup.6   na                                                                              nb                                                                              salt point                  __________________________________________________________________________                                                           (°C.)            2                                                                                   ##STR11##           H H H H                                                                                 ##STR12##                                                                              1 1 HCl  184-185  EtOH!         .sup.   3*.sup.a                                                                     ##STR13##           " " " "  "         " " "    174.5-175  Me.sub.2                                                            COEtOH!                     (R-form)                                                                .sup.   4*.sup.b                                                                     ##STR14##           H H H H                                                                                 ##STR15##                                                                              1 1 HCl  174.5-175  Me.sub.2                                                            COEtOH!                     (S-form)                                                                 5                                                                                   ##STR16##           " " " "                                                                                 ##STR17##                                                                              " " --   Oily                    6    "                    " " " "                                                                                 ##STR18##                                                                              " " HCl  173-174  EtOHEt.sub                                                           .2 O!                   7    "                    " " " "                                                                                 ##STR19##                                                                              " " "    163.5-164.5                                                                    EtOHEt.sub.2 O!        8                                                                                   ##STR20##           H H H H                                                                                 ##STR21##                                                                              1 1 HCl  153-154.5  EtOHEt.s                                                           ub.2 O!                 9    "                    " " " "                                                                                 ##STR22##                                                                              " " --   Oily                    10   "                    " " " "                                                                                 ##STR23##                                                                              " " "    "                       11   "                    " " " "                                                                                 ##STR24##                                                                              " " "    "                       12                                                                                  ##STR25##           H H H H                                                                                 ##STR26##                                                                              2 1 --   Oily                    13   "                    " " " "  "         3 3 HCl  Amorphous               14                                                                                  ##STR27##           " " " "  "         1 1 "    198-199  EtOH!          15                                                                                  ##STR28##           " " " "  "         " " "    165-166  IPA!           16                                                                                  ##STR29##           H H H H                                                                                 ##STR30##                                                                              1 1 HCl  181.5-183  EtOH!        17                                                                                  ##STR31##           " " " "  "         " " "    201.5-203  IPA!         18                                                                                  ##STR32##           " " " "  "         " " "    194.5-196.5                                                                    EtOH!                  19                                                                                  ##STR33##           " " " "  "         " " "    251-252  EtOH!          20                                                                                  ##STR34##           H H H H                                                                                 ##STR35##                                                                              1 1 HCl  141-143  EtOHEt.sub                                                           .2 O!                   21   "                    " " " "                                                                                 ##STR36##                                                                              " " "    136.5-137.5                                                                    EtOHEt.sub.2 O!        22   "                    " " " "                                                                                 ##STR37##                                                                              " " --   Oily                    23   "                    " " " "                                                                                 ##STR38##                                                                              2 2 "    "                       24                                                                                  ##STR39##           H H H H                                                                                 ##STR40##                                                                              1 2 --   Oily                    25   "                    " " " "                                                                                 ##STR41##                                                                              " 1 "    "                       26                                                                                  ##STR42##           " " " "                                                                                 ##STR43##                                                                              " " HCl  184-185  EtOH!          27                                                                                  ##STR44##           " " " "  "         " " "    158-159  IPA!           28                                                                                  ##STR45##           H H Me                                                                              H                                                                                 ##STR46##                                                                              1 1 --   Oily                    29   "                    " " H Me "         " " "    "                       30                                                                                  ##STR47##           " Me                                                                              " H  "         " " HCl  190-191  MeOHEt.sub                                                           .2 O!                   31                                                                                  ##STR48##           " H " "  "         " " "    203-204  EtOH!          32                                                                                  ##STR49##           H H H H                                                                                 ##STR50##                                                                              1 1 HCl  170-171  Me.sub.2                                                             CO!                     33                                                                                  ##STR51##           " " " "  "         " " "    188.5-190  MeOHEt.s                                                           ub.2 O!                 34                                                                                  ##STR52##           " " " "  "         " " "    156.5-157.5                                                                    EtOHEt.sub.2 O!        35                                                                                  ##STR53##           " " " "  "         " " "    184-184.5  EtOH!        36                                                                                  ##STR54##           H H H H                                                                                 ##STR55##                                                                              1 1 HCl  131--132  EtOHEt.su                                                           b.2 O!                  37                                                                                  ##STR56##           " " " "  "         " " "    178.5-179.5                                                                    EtOHEt.sub.2 O!        38                                                                                  ##STR57##           " " " "                                                                                 ##STR58##                                                                              " " "    171-172  EtOH!          39                                                                                  ##STR59##           " " " "  "         " " "    182-182.5  EtOH!        40                                                                                  ##STR60##           H H H H                                                                                 ##STR61##                                                                              1 1 HCl  228-229.5  EtOHEt.s                                                           ub.2 O!                 41                                                                                  ##STR62##           " " " "  "         " " "    193.5-194.5                                                                    EtOH!                  42                                                                                  ##STR63##           " " " "  "         " " "    168.5-169.5                                                                    EtOHEt.sub.2 O!        43                                                                                  ##STR64##           " " " "  "         " " "    146-147  EtOH!          44                                                                                  ##STR65##           H H H H                                                                                 ##STR66##                                                                              1 1 HCl  171-173  EtOH!          45                                                                                  ##STR67##           " " " "  "         " " PTS  140-141  EtOH!          46                                                                                  ##STR68##           " " " "  "         " " HCl  179.5-181.5                                                                    EtOHEt.sub.2 O!        47                                                                                  ##STR69##           " " " "  "         " " "    169-171  EtOH!          48                                                                                  ##STR70##           H H H H                                                                                 ##STR71##                                                                              1 1 HCl  186-186.5  EtOH!        49                                                                                  ##STR72##           " " " "  "         " " "    188-188.5  EtOH!        50                                                                                  ##STR73##           " " " "  "         " " "    199-199.5  MeOHEtOH                                                           !                       51                                                                                  ##STR74##           " " " "  "         " " --   Oily                    52                                                                                  ##STR75##           H H H H                                                                                 ##STR76##                                                                              1 1 HCl  149.5-151  Me.sub.2                                                            CO!                    53                                                                                  ##STR77##           " " " "  "         " " "    140-141  EtOHEt.sub                                                           .2 O!                   54                                                                                  ##STR78##           " " " "  "         " " "    174.5-176.5                                                                    MeCN!                  55                                                                                  ##STR79##           " " " "  "         " " "    229-231  MeCN!          56                                                                                  ##STR80##           H H H H                                                                                 ##STR81##                                                                              1 1 HCl  217.5-218.5                                                                    EtOH!                  57                                                                                  ##STR82##           " " " "  "         " " "    138-140  EtOHEt.sub                                                           .2 O!                   58                                                                                  ##STR83##           " " " "  "         " " "    153-154  EtOH!          59                                                                                  ##STR84##           " " " "  "         " " "    179-181  EtOH!          60                                                                                  ##STR85##           H H H H                                                                                 ##STR86##                                                                              1 1 --   Oily                    61                                                                                  ##STR87##           " " " "  "         " " "    "                       62                                                                                  ##STR88##           " " " "  "         " " "    50-52                   63                                                                                  ##STR89##           " " " "                                                                                 ##STR90##                                                                              " " HCl  160-161  EtOHEt.sub                                                           .2 O!                   64                                                                                  ##STR91##           H H H H                                                                                 ##STR92##                                                                              1 1 HCl  151-152.5  EtOHEt.s                                                           ub.2 O!                 65                                                                                  ##STR93##           " " " "                                                                                 ##STR94##                                                                              " " "    223-225  EtOHIPA!       66                                                                                  ##STR95##           " " " "  "         " " "    215-216  MeOHEtOH!      67                                                                                  ##STR96##           " " " "  "         " " "    180.5-181.5                                                                    MeCN!                  68                                                                                  ##STR97##           H H H H                                                                                 ##STR98##                                                                              1 1 HCl  168.5-169.5  IPA!       69                                                                                  ##STR99##           " " " "  "         " " "    177.5-178.5                                                                    MeCN!                  70                                                                                  ##STR100##          " " " "  "         " " "    194.5-195  MeCN!        71                                                                                  ##STR101##          " " " "  "         " " "    162-162.5  IPA!         72                                                                                  ##STR102##          H H H H                                                                                 ##STR103##                                                                             1 1 HCl  171-172  IPA!           73                                                                                  ##STR104##          " " " "  "         " " "    162-162.5  IPA!         74                                                                                  ##STR105##          " " " "  "         " " "    147.5-148.5                                                                    Me.sub.2 COEt.sub.                                                           2 O!                    75                                                                                  ##STR106##          " " " "  "         2 " --   Oily                    76                                                                                  ##STR107##          H H H H                                                                                 ##STR108##                                                                             1 1 HCl  160-160.5  IPA!         77   "                    " " " "                                                                                 ##STR109##                                                                             " " "    192.5-193  MeCN!        78   "                    " " " "                                                                                 ##STR110##                                                                             " " --   Oily                    79                                                                                  ##STR111##          " " " "                                                                                 ##STR112##                                                                             " " HCl  124-125  MeCN!          80                                                                                  ##STR113##          H H H H                                                                                 ##STR114##                                                                             2 1 --   121.5-123  AcOEtEt.                                                           sub.2 O!                81                                                                                  ##STR115##          " " " "  "         1 " "    Oily                   .sup.  82*.sup.c                                                                     ##STR116##          " " " "  "         " " HCl  179-181  EtOH!          83                                                                                  ##STR117##          " " " "  "         " " "    189.5-190  IPA!         84                                                                                  ##STR118##          H H H H                                                                                 ##STR119##                                                                             1 1 2HCl 157-158  EtOH!          85                                                                                  ##STR120##          " " " "  "         " " HCl  161-162.5  IPA!         86                                                                                  ##STR121##          " " " "  "         " " 2HCl 157.5-159.5                                                                    EtOH!                  87                                                                                  ##STR122##          " " " "  "         " " HCl  172-173  IPA!           88                                                                                  ##STR123##          H H H H                                                                                 ##STR124##                                                                             1 1 --   Oily                    89                                                                                  ##STR125##          " " " "                                                                                 ##STR126##                                                                             " " HCl  222.5-223.5                                                                    EtOH!                  90                                                                                  ##STR127##          " " " "                                                                                 ##STR128##                                                                             " " --   Oily                    91                                                                                  ##STR129##          " " " "                                                                                 ##STR130##                                                                             " " HCl  204.5-205  EtOHMe.s                                                           ub.2 CO!                92                                                                                  ##STR131##          H H H H                                                                                 ##STR132##                                                                             1 1 HCl  168.5-169  EtOHAcOE                                                           t!                      93                                                                                  ##STR133##          " " " "  "         " " "    193-194  EtOHAcOEt!     94                                                                                  ##STR134##          " " " "  "         " " "    154.5-156  MeCN!        95                                                                                  ##STR135##          " " " "  "         " " "    168.5-169.5                                                                    EtOHAcOEt!             96                                                                                  ##STR136##          H H H H                                                                                 ##STR137##                                                                             1 1 HCl  197-198  IPAAcOEt!                                                            N                       97                                                                                  ##STR138##          " " " "  "         " " "    176-178  EtOH!          98                                                                                  ##STR139##          " " " "  "         " " "    140.5-142  IPA!         99                                                                                  ##STR140##          " " " "  "         " " "    181.5-182.5                                                                    EtOH!                 100                                                                                  ##STR141##          H H H H                                                                                 ##STR142##                                                                             1 1 HCl  170-170.5  EtOHMe.s                                                           ub.2 CO!               101                                                                                  ##STR143##          " " " "                                                                                 ##STR144##                                                                             " " "    199-199.5  EtOH!       .sup.  102*.sup.d                                                                    ##STR145##          " " " "  NH.sub.2  " " 1/2 Fumaric acid                                                                   181-182.5              .sup.  103*.sup.e                                                                    ##STR146##          " " " "                                                                                 ##STR147##                                                                             " " HCl  194-194.5  EtOHMe.s                                                           ub.2 CO!                     (R-form)                                                                  104*.sup.f                                                                         ##STR148##          H H H H                                                                                 ##STR149##                                                                             1 1 HCl  164-165  EtOHMe.sub                                                           .2 CO!                       (R-form)                                                                .sup.  105*.sup.g                                                                    ##STR150##          " " " "  "         " " "    193-194  MeCN!               (R-form)                                                                .sup.  106*.sup.h                                                                    ##STR151##          " " " "                                                                                 ##STR152##                                                                             " " 1/2 1,5- Naphtha-                                                             lenedi- sulfonic                                                                   Amorphous              .sup.  107*.sup.i                                                                    ##STR153##          " " " "                                                                                 ##STR154##                                                                             " " HCl  195-196  EtOHMe.sub                                                           .2 CO!                       (S-form)                                                                .sup.  108*.sup.j                                                                    ##STR155##          H H H H                                                                                 ##STR156##                                                                             1 1 HCl  163-164.5  EtOHMe.s                                                           ub.2 CO!                     (S-form)                                                                .sup.  109*.sup.k                                                                    ##STR157##          " " " "  "         " " "    187.5-188.5                                                                    MeCN!                       (S-form)                                                                .sup.  110*.sup.h                                                                    ##STR158##          " " " "                                                                                 ##STR159##                                                                             " " 1/2 1,5- Naphtha-                                                             lenedi- sulfonic                                                                   168-170 (decomp.)      111                                                                                  ##STR160##          " " " "                                                                                 ##STR161##                                                                             " " --   Oily                   112                                                                                  ##STR162##                                      171-173  EtOHEt.sub                                                           .2 O!                  __________________________________________________________________________     Note:                                                                         *.sup.a : Optical rotation: -43.3° (27° C., C = 3, EtOH)        *.sup.b : Optical rotation: +43.3° (24° C., C = 3, EtOH)        *.sup.c : Obtained by treating compound No. 81 with ptoluenesulfonic acid     *.sup.d : A trityl group was used as an aminoprotecting group.                *.sup.e : Optical rotation: -38.9° (28° C., C = 1.5, MeOH)      *.sup.f : Optical rotation: -45.8° (25° C., C = 1.5, MeOH)      *.sup.g : Optical rotation: -38.5° (25° C., C = 1.5, EtOH)      *.sup.h : Obtained by reacting 1 mole of a dimethylamino form with 0.5        mole of dimethyl 1,5naphthalenedisulfonate.                                   *.sup.i : Optical rotation: +37.3° (23° C., C = 1.5, MeOH)      *.sup.j : Optical rotation: +40.2° (23° C.; C = 1.5, MeOH)      *.sup.k : Optical rotation: +28.4° (23° C., C = 1.5, EtOH) 

Production Example 4

A mixture of 5.00 g of 1-benzyl-4-hydroxypiperidine, 1.97 g of potassiumtert-butoxide and 4 ml of dimethyl sulfoxide was heated to 80° C.Thereto was dropwise added 2.10 g of styrene oxide over 40 minutes. Theresulting mixture was stirred for 3 hours at the same temperature. Thereaction mixture was added to a mixture of 100 ml of ice water and 80 mlof ethyl acetate. The mixture was adjusted to pH 11.5 with 6Nhydrochloric acid. The organic layer was separated, washed with waterand a saturated aqueous sodium chloride solution in this order, anddried over anhydrous magnesium sulfate. The solvent was removed bydistillation under reduced pressure. The residue thus obtained waspurified by column chromatography (eluant: chloroform/ethanol=10/1). Theresulting oily product was dissolved in 8 ml of ethanol. To the solutionwere added 1 ml of a 6N dry hydrogen chloride-ethanol solution and 20 mlof diethyl ether. The mixture was stirred for 30 minutes at roomtemperature. The resulting crystals were collected by filtration, washedwith a mixture of 2 ml of ethanol and 2 ml of diethyl ether, and driedto obtain 930 mg of 2-(1-benzylpiperidin-4-yloxy)-1-phenylethanolhydrochloride (compound No. 113).

Melting point: 193°-195° C.

The compounds shown in Table 6 were obtained in the same manner.

In Table 6, R¹, R², R³, R⁴, R⁶ and n each show a substituent or integerused in the following formula:

                                      TABLE 6                                     __________________________________________________________________________     ##STR163##                                                                   Compound                          Addition                                                                           Melting                                No.   R.sup.1   R.sup.2                                                                         R.sup.3                                                                         R.sup.4                                                                         R.sup.6   n salt point (°C.)                     __________________________________________________________________________    114                                                                                  ##STR164##                                                                             H H --                                                                               ##STR165##                                                                             0 HCl  180-181.5  IPA!                        115   "         " " "                                                                                ##STR166##                                                                             " "    202-204                                116                                                                                  ##STR167##                                                                             " " "                                                                                ##STR168##                                                                             " --   119-120                                117                                                                                  ##STR169##                                                                             H H H                                                                                ##STR170##                                                                             1 HCl  153-155  Me.sub.2 COEtOH!              118   "         " " "                                                                                ##STR171##                                                                             " "    Oily                                   119   "         " " "                                                                                ##STR172##                                                                             " --   92-95                                  120   "         " " "                                                                                ##STR173##                                                                             " HCl  Oily                                   121                                                                                  ##STR174##                                                                             H H H                                                                                ##STR175##                                                                             1 --   78-81  AcOEtIPE!                       122                                                                                  ##STR176##                                                                             " " "                                                                                ##STR177##                                                                             " HCl  129.5-131.5  AcOEtIPE!                 123   "         " " "                                                                                ##STR178##                                                                             " "    157.5-159.5                            124   "         " " "                                                                                ##STR179##                                                                             " "    137-138.5  Me.sub.2 CO!                125                                                                                  ##STR180##                                                                             H H H                                                                                ##STR181##                                                                             1 HCl  Oily                                   126                                                                                  ##STR182##                                                                             " " " "         " "    "                                      127                                                                                  ##STR183##                                                                             " " "                                                                                ##STR184##                                                                             " "    "                                      128   "         " " "                                                                                ##STR185##                                                                             " --   "                                      .sup.  129*.sup.1                                                                    ##STR186##                                                                             H H H                                                                                ##STR187##                                                                             1 --   61-61.5  EtOHIPE!                      .sup.  130*.sup.2                                                                    ##STR188##                                                                             " " " "         " "    61-61.5  EtOHIPE!                      131                                                                                  ##STR189##                                                                             " " " "         " "    71.5-72  EtOHIPE!                      .sup.  132*.sup.3                                                                    ##STR190##                                                                             " " "                                                                                ##STR191##                                                                             " "    118-119.5                              .sup.  133*.sup.3                                                                    ##STR192##                                                                             H H H                                                                                ##STR193##                                                                             1 HCl  147.5-149  IPAAcOEt!                   .sup.  134*.sup.3                                                                    ##STR194##                                                                             " " "                                                                                ##STR195##                                                                             " "    Oily                                   .sup.  135*.sup.3                                                                    ##STR196##                                                                             " " "                                                                                ##STR197##                                                                             " "    104.5-106.5  IPAAcOEt!                 .sup. "136*.sup.3                                                                             " " "                                                                                ##STR198##                                                                             " "    220-221  EtOHAcOEt!                    .sup.  137*.sup.3                                                                    ##STR199##                                                                             H H H                                                                                ##STR200##                                                                             1 --   154-156  IPAAcOEt!                     .sup.  138*.sup.4                                                                    ##STR201##                                                                             " " "                                                                                ##STR202##                                                                             " 2HCl 241-242 (decomp.)                      139                                                                                  ##STR203##                                                                             " " "                                                                                ##STR204##                                                                             " --   53.5-54.5  Et.sub.2 O!                 140                                                                                  ##STR205##                                                                             " " " "         3 "    Oily                                   141                                                                                  ##STR206##                                                                             H H H                                                                                ##STR207##                                                                             1 --   84.5-85.5  EtOHIPE!                    142                                                                                  ##STR208##                                                                             " " " "         " "    65.5-66.5  EtOHIPE!                    143                                                                                  ##STR209##                                                                             " " " "         " "    68-69  EtOHIPE!                        __________________________________________________________________________     Note:                                                                         *.sup.1 : Optical rotation: +23.3° (25° C., C = 1, MeOH)        *.sup.2 : Optical rotation: -22.5° (25° C., C = 1, MeOH)        *.sup.3 : The reaction was effected using a trityl group as an                aminoprotecting group.                                                        *.sup.4 : The reaction was effected using a formyl group as an                aminoprotecting group.                                                   

Production Example 5

(1) A mixture of 4.30 g of 4-benzyl-2-hydroxymethylmorpholine, 930 mg ofpotassium tert-butoxide and 4 ml of dimethyl sulfoxide was heated to 80°C. Thereto was dropwise added 2.50 g of styrene oxide over 20 minutes.The resulting mixture was stirred for 2 hours at the same temperature.The reaction mixture was added to a mixture of 30 ml of diethyl etherand 30 ml of ice water. The organic layer was separated and mixed with10 ml of water. The mixture was adjusted to pH 2.0 with 6N hydrochloricacid. The aqueous layer was separated and mixed with 30 ml of diethylether. The mixture was adjusted to pH 11 with a 2N aqueous sodiumhydroxide solution. The organic layer was separated, washed with asaturated aqueous sodium chloride solution, and dried over anhydrousmagnesium sulfate. The solvent was removed by distillation under reducedpressure. The residue was purified by column chromatography (eluant:toluene/ethyl acetate=1/1) to obtain 2.00 g of oily 1-phenyl-2-(4-benzylmorpholin-2-yl)methoxy!ethanol (compound No. 144).

The compounds shown in Table 7 were obtained in the same manner.

In Table 7, R¹, R², R³, R⁴, R⁶ and n each show a substituent or integerused in the following formula:

                                      TABLE 7                                     __________________________________________________________________________     ##STR210##                                                                   Compound                        Addition                                                                           Melting                                  No.   R.sup.1   R.sup.2                                                                         R.sup.3                                                                         R.sup.4                                                                         R.sup.6 n salt point (°C.)                       __________________________________________________________________________    145                                                                                  ##STR211##                                                                             H H H                                                                                ##STR212##                                                                           1 --   Oily                                     146                                                                                  ##STR213##                                                                             " " " "       " "    "                                        147                                                                                  ##STR214##                                                                             " " " "       " "    "                                        148                                                                                  ##STR215##                                                                             " " "                                                                                ##STR216##                                                                           " "    "                                        149                                                                                  ##STR217##                                                                             H H H                                                                                ##STR218##                                                                           1 --   Oily                                     150                                                                                  ##STR219##                                                                             " " " "       " "    "                                        __________________________________________________________________________

(2) A mixture of 1.00 g of 1-phenyl-2-(4-benzylmorpholin-2-yl)methoxy!ethanol, 500 mg of 5% palladium-carbonand 10 ml of methanol was subjected to hydrogenation for 4 hours at roomtemperature under atmospheric pressure. After the completion of thereaction, palladium-carbon was removed by filtration. The solvent wasremoved by distillation under reduced pressure. The residue was purifiedby column chromatography (eluant: chloroform/methanol=10/1) to obtain450 mg of an oily product. The oily product was dissolved in 2.5 ml ofisopropanol. The solution was mixed with 220 mg of fumaric acid. Themixture was stirred for 1 hour at room temperature. The resultingcrystals were collected by filtration, washed with 2 ml of isopropanoland dried to obtain 460 mg of 1/2 fumarate of 1-phenyl-2-(morpholin-2-yl)methoxy!ethanol (compound No. 151).

Melting point: 146.5°-147° C. EtOH!

The compounds shown in Table 8 were obtained in the same manner.

In Table 8, R¹, R², R³, R⁴, R⁶ and n each show a substituent or integerused in the following formula:

                                      TABLE 8                                     __________________________________________________________________________     ##STR220##                                                                   Compound                       Addition                                                                           Melting                                   No.   R.sup.1   R.sup.2                                                                         R.sup.3                                                                         R.sup.4                                                                         R.sup.6                                                                              n salt point (°C.)                        __________________________________________________________________________    152                                                                                  ##STR221##                                                                             H H H                                                                                ##STR222##                                                                          1 1/2 Fumaric acid                                                                   155-156  EtOH!                            153                                                                                  ##STR223##                                                                             " " " "      " HCl  Amorphous                                 154                                                                                  ##STR224##                                                                             " " " "      " 1/2 Fumaric acid                                                                   142-142.5  EtOHMe.sub.2 CO!               __________________________________________________________________________

(3) 7 g of 1-(3-methoxyphenyl)-2-(4-tritylmorpholin-2-yl)methoxy!ethanol was dissolved in 35 ml ofacetone. To the solution was added 2.6 ml of a 5.9N dry hydrogenchloride-ethanol solution with ice cooling. The mixture was stirred for2 hours at room temperature. After the completion of the reaction, thesolvent was removed by distillation under reduced pressure. To theresidue thus obtained were added 50 ml of water and 30 ml of ethylacetate. The aqueous layer was separated and washed with ethyl acetate.Thereto was added 50 ml of chloroform. The resulting mixture wasadjusted to pH 11 with a 1N aqueous sodium hydroxide solution. Theorganic layer was separated and dried over anhydrous magnesium sulfate.The solvent was removed by distillation under reduced pressure. Theresidue thus obtained was purified by column chromatography (eluant:chloroform/methanol=5/1) to obtain 1 g of an oily product. The oilyproduct was dissolved in 3 ml of isopropanol. Thereto was added 430 mgof fumaric acid. The mixture was stirred for 1 hour at room temperature.The resulting crystals were collected by filtration and dried to obtain800 mg of 1/2 fumarate of 1-(3-methoxyphenyl)-2-(morpholin-2-yl)methoxy!ethanol (compound No. 155).

Melting point: 122°-123.5° C. EtOH!

The compounds shown in Table 9 were obtained in the same manner.

In Table 9, R¹, R², R³, R⁴, R⁶ and n each show a substituent or integerused in the following formula:

                                      TABLE 9                                     __________________________________________________________________________     ##STR225##                                                                   Compound                       Addition                                                                           Melting                                   No.   R.sup.1   R.sup.2                                                                         R.sup.3                                                                         R.sup.4                                                                         R.sup.6                                                                              n salt point (°C.)                        __________________________________________________________________________    156                                                                                  ##STR226##                                                                             H H H                                                                                ##STR227##                                                                          1 1/2 Fumaric acid                                                                   147-148.5  EtOH!                          157                                                                                  ##STR228##                                                                             " " " "      " 1/2 Fumaric acid                                                                   126-127  IPA!                             __________________________________________________________________________

Production Example 6

(1) 5.1 g of potassium tert-butoxide was added to 105 ml of ethyleneglycol mono-tert-butyl ether. The mixture was heated to 80° C. Theretowas dropwise added 35.0 g of 2-(3-chlorophenyl)oxirane over 1 hour. Themixture was stirred for 2 hours at the same temperature. The reactionmixture was added to a mixture of 100 ml of ice water and 100 ml ofethyl acetate. The organic layer was separated, washed with a saturatedaqueous sodium chloride solution, and dried over anhydrous magnesiumsulfate. The solvent was removed by distillation under reduced pressure.The residue thus obtained was subjected to further distillation underreduced pressure to obtain 37.7 g of colorless oily1-(3-chlorophenyl)-2-(2-tert-butoxyethoxy)ethanol having a boiling pointof 140°-146° C./0.9 mm Hg.

(2) 37.0 g of 1-(3-chlorophenyl)-2-(2-tert-butoxyethoxy)ethanol wasdissolved in 70 ml of methylene chloride. To the solution were added12.9 g of pyridine and 16.6 g of acetic anhydride. The resulting mixturewas stirred for 24 hours at room temperature. The reaction mixture wasadded to a mixture of 150 ml of ice water and 100 ml of methylenechloride. The resulting mixture was adjusted to pH 2 with 6Nhydrochloric acid. The organic layer was separated, washed with asaturatred aqueous sodium hydrogencarbonate solution and water in thisorder, and dried over anhydrous magnesium sulfate. The solvent wasremoved by distillation under reduced pressure to obtain 40.0 g of oily1-acetoxy-1-(3-chlorophenyl)-2-(2-tert-butoxyethoxy)ethane.

(3) 40.0 g of 1-acetoxy-l-(3-chlorophenyl)-2-(2-tert-butoxyethoxy)ethanewas dissolved in 40 ml of methylene chloride. To the solution was added80 ml of trifluoroacetic acid with ice cooling. The mixture was stirredfor 12 hours at room temperature. After the completion of the reaction,the solvent was removed by distillation under reduced pressure. Theresidue was mixed with 100 ml of toluene. The solvent was furtherremoved by distillation under reduced pressure. The residue thusobtained was dissolved in a mixture of 90 ml of ethanol and 10 ml ofwater. To the solution was added 10.7 g of sodium hydrogencarbonate atroom temperature. The mixture was adjusted to pH 6-7 with a saturatedaqueous sodium hydrogencarbonate solution, and then concentrated toabout a half volume under reduced pressure. To the concentrate was added100 ml of ethyl acetate. The organic layer was separated. The aqueouslayer was extracted with 50 ml of ethyl acetate. The extract wascombined with the previously separated organic layer. The combinedorganic layer was washed with a saturated aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate. The solvent wasremoved by distillation under reduced pressure. The residue was purifiedby column chromatography (eluant: toluene/ethyl acetate=3/1) to obtain19.4 g of oily 1-acetoxy-1-(3-chlorophenyl)-2-(2-hydroxyethoxy)ethane.

(4) To a mixture of 19.0 g of1-acetoxy-1-(3-chlorophenyl)-2-(2-hydroxyethoxy)ethane and 95.0 ml ofmethylene chloride containing 9.1 ml of methanesulfonyl chloride wasdropwise added 16.4 ml of triethylamine with ice cooling over 1 hour.The resulting mixture was stirred for 10 minutes at the same temperatureand further for 1 hour at room temperature. The reaction mixture wasadded to a mixture of 50.0 ml of methylene chloride and 50.0 ml of icewater. The resulting mixture was adjusted to pH 2.0 with 6N hydrochloricacid. The organic layer was separated, washed with water and dried overanhydrous magnesium sulfate. The solvent was removed by distillationunder reduced pressure to obtain 24.5 g of oily1-acetoxy-1-(3-chlorophenyl)-2-(2-methanesulfonyloxyethoxy)ethane.

(5) 1.40 g of1-acetoxy-1-(3-chlorophenyl)-2-(2-methanesulfonyloxyethoxy)ethane wasdissolved in 7 ml of N,N-dimethylformamide. To the solution were added0.69 ml of N-methylpiperazine and 1.03 g of potassium carbonate. Themixture was stirred for 3 hours at 80° C. The reaction mixture wascooled and added to a mixture of 30 ml of ice water and 30 ml of diethylether. The organic layer was separated. The aqueous layer was extractedwith 20 ml of diethyl ether. The extract was combined with thepreviously separated organic layer. The combined organic layer waswashed with water and a saturated aqueous sodium chloride solution inthis order, and dried over anhydrous magnesium sulfate. The solvent wasremoved by distillation under reduced pressure. The residue thusobtained was mixed with 7 ml of methanol and 45 mg of sodium methoxide.The mixture was allowed to stand overnight at room temperature. Thesolvent was removed by distillation under reduced pressure. To theresidue thus obtained were added 20 ml of ethyl acetate and 10 ml ofwater. The organic layer was separated. The aqueous layer was extractedwith 20 ml of ethyl acetate. The extract was combined with thepreviously separated organic layer. The combined organic layer waswashed with a saturated aqueous sodium chloride solution and thenpurified by column chromatography (eluant: chloroform/methanol=10/1). Tothe resulting oily product were added 10 ml of ethanol and 1.2 ml of a6N dry hydrogen chloride-ethanol solution in this order. To theresulting mixture was added 10 ml of diethyl ether. The mixture wasstirred for 30 minutes. The resulting crystals were collected byfiltration, washed with a mixture of 2 ml of ethanol and 2 ml of diethylether, and dried to obtain 770 mg of 1-(3-chlorophenyl)-2-2-(4-methylpiperazin-1-yl)ethoxy!ethanol dihydrochloride (compound No.158).

Melting point: 211°-213° C. MeOH-EtOH!

The compounds shown in Table 10 were obtained in the same manner.

In Table 10, R¹, R², R³, R⁴, R⁶ and n each show a substituent or integerused in the following formula:

                                      TABLE 10                                    __________________________________________________________________________     ##STR229##                                                                   Compound                          Addition                                                                           Melting                                No.   R.sup.1                                                                              R.sup.2                                                                         R.sup.3                                                                         R.sup.4                                                                         R.sup.6      n salt point (°C.)                     __________________________________________________________________________    159                                                                                  ##STR230##                                                                          H H H                                                                                ##STR231##  2 --   Oily                                   160   "      " " "                                                                                ##STR232##  " "    134.5-136.5  IPA!                      161   "      " " "                                                                                ##STR233##  " "    Oily                                   162   "      " " "                                                                                ##STR234##  " HCl  138-140  IPA!                          163                                                                                  ##STR235##                                                                          H H H                                                                                ##STR236##  2 --   Oily                                   164   "      " " "                                                                                ##STR237##  " HCl  164.5-166.5                            165   "      " " "                                                                                ##STR238##  " "    169-171  EtOH!                         166   "      " " "                                                                                ##STR239##  " 2HCl 169-171  CH.sub.2 Cl.sub.2 EtOH!       167   "      " " "                                                                                ##STR240##  " --   104.5-105.5  EtOH!                     168                                                                                  ##STR241##                                                                          H H H                                                                                ##STR242##  2 --   Oily                                   .sup. "169*.sup.a                                                                          " " "                                                                                ##STR243##  " 1/2 1,5- Naphtha- lenedi- sulfonic                                                 208-210  MeOHEt.sub.2 O!               __________________________________________________________________________     Note:                                                                         *.sup.a 1 mole of a dimethylamino form was reacted with 0.5 mole of           dimethyl 1,5naphthalenedisulfonate, to obtain the desired product.       

Production Example 7

A mixture of 2.0 g of 1-(4-benzyloxyphenyl)-2-2-(N,N-dimethylamino)ethoxy!ethanol hydrochloride, 500 mg of 10%palladium-carbon and 10 ml of methanol was subjected to hydrogenationfor 2 hours at room temperature under atmospheric pressure. After thecompletion of the reaction, palladium-carbon was removed by filtration.The solvent was removed by distillation under reduced pressure to obtain1.4 g of 1-(4-hydroxyphenyl)-2- 2-(N,N-dimethylamino)ethoxy!ethanolhydrochloride (Compound No. 170).

Melting point: 169.5°-170.5° C. EtOH!

The compounds shown in Table 11 were obtained in the same manner.

In Table 11, R¹, R², R³, R⁴, R⁶ and n each show a substituent or integerused in the following formula:

                                      TABLE 11                                    __________________________________________________________________________     ##STR244##                                                                   Compound                         Addition                                                                           Melting                                 No.   R.sup.1   R.sup.2                                                                         R.sup.3                                                                         R.sup.4                                                                         R.sup.6  n salt point (°C.)                      __________________________________________________________________________    171                                                                                  ##STR245##                                                                             H H H                                                                                ##STR246##                                                                            2 HCl  150-152  EtOH!                          172   "         Ac                                                                              " " "        " "    Amorphous                               173                                                                                  ##STR247##                                                                             H " " "        " --   Oily                                    174                                                                                  ##STR248##                                                                             " " "                                                                                ##STR249##                                                                            " HCl  145-147                                 175                                                                                  ##STR250##                                                                             H H H                                                                                ##STR251##                                                                            2 2HCl 204.5- 206.5  MeOH!                     176                                                                                  ##STR252##                                                                             " " "                                                                                ##STR253##                                                                            " --   Oily                                    177                                                                                  ##STR254##                                                                             " " "                                                                                ##STR255##                                                                            " HCl  151-153                                 __________________________________________________________________________

Production Example 8

0.65 ml of pyridine and 0.99 ml of acetic anhydride were added to 1 g of1'-(3-methylphenyl)-2- 2-(morpholin-4-yl)ethoxy!ethanol. The mixture wasstirred for 3 hours at room temperature. The reaction mixture wassubjected to distillation under reduced pressure to remove the solvent.To the residue were added 20 ml of ethyl acetate and 10 ml of water. Themixture was adjusted to pH 10 with potassium carbonate. The organiclayer was separated, washed with water and a saturated aqueous sodiumchloride solution in this order, and dried over anhydrous magnesiumsulfate. The solvent was removed by distillation under reduced pressure.The residue was purified by column chromatography (eluant:chloroform/ethanol=30/1) to obtain 1 g of oily1-acetoxy-1-(3-methylphenyl)-2- 2-(morpholin-4-yl)ethoxy!ethane(compound No. 178).

The compounds shown in Table 12 were obtained in the same manner.

In Table 12, R¹, R², R³, R⁴, R⁶ and n each show a substituent or integerused in the following formula:

                                      TABLE 12                                    __________________________________________________________________________     ##STR256##                                                                   Compound                       Addition                                                                           Melting                                   No.   R.sup.1   R.sup.2                                                                         R.sup.3                                                                         R.sup.4                                                                         R.sup.6                                                                              n salt point (°C.)                        __________________________________________________________________________    179                                                                                  ##STR257##                                                                             Ac                                                                              H H                                                                                ##STR258##                                                                          2 --   Oily                                      180   "         " " "                                                                                ##STR259##                                                                          " "    "                                         .sup.  181*.sup.d                                                                    ##STR260##                                                                             H " "                                                                                ##STR261##                                                                          " "    "                                         .sup.  182*.sup.e                                                                    ##STR262##                                                                             " " "                                                                                ##STR263##                                                                          " HCl  174.5-176.5  EtOH!                        183                                                                                  ##STR264##                                                                             Ac                                                                              H H                                                                                ##STR265##                                                                          2 HCl  169.5- 170.5  EtOH!                       184                                                                                  ##STR266##                                                                             " " " "      " "    131.5- 132.5  Me.sub.2 CO!                185                                                                                  ##STR267##                                                                             " " " "      " "    Oily                                      186                                                                                  ##STR268##                                                                             " " " "      " --   Oily                                      187                                                                                  ##STR269##                                                                             " " " "      " "    144.5- 146.5  EtOHEt.sub.2 O!             188                                                                                  ##STR270##                                                                             Ac                                                                              H H                                                                                ##STR271##                                                                          1 HCl  Oily                                      __________________________________________________________________________     Note:                                                                         *.sup.d The indicated compound was obtained by reacting compound No. 174      with acetic anhydride.                                                        *.sup.e The indicated compound was obtained by reacting compound No. 177      with benzenesulfonyl chloride in pyridine.                               

Production Example 9

50 ml of a 1:1 mixture of chloroform and water was added to 3.30 g of1-acetoxy-1-(3-hydroxyphenyl)-2- 2-(N,N-dimethylamino)ethoxy!ethanehydrochloride. To the mixture was added 750 mg of sodium carbonate withice cooling. The organic layer was separated and dried with anhydrousmagnesium sulfate. The solvent was removed by distillation under reducedpressure. The residue was mixed with 20 ml of benzene. The mixture washeated to 60° C. To the resulting solution was dropwise added a solutionof 870 mg of ethyl isocyanate dissolved in 5 ml of benzene in 10minutes. The mixture was stirred for 40 minutes at the same temperature.After the completion of the reaction, the solvent was removed bydistillation under reduced pressure. The residue thus obtained waspurified by column chromatography (eluant: chloroform/ethanol=10/1) toobtain an oily product. The oily product was dissolved in 10 ml ofethanol. Hydrogen chloride gas was blown into the solution. The solventwas removed by distillation under reduced pressure to obtain 1.90 g of1-acetoxy-1- 3-(N-ethylcarbamoyloxy)phenyl!-2-2-(N,N-dimethylamino)ethoxy!ethane hydrochloride (compound No. 189).

Melting point: 111.5°-113.5° C. Me₂ CO!

In the same manner, there was obtained oily 1-acetoxy-1-3-(3-chlorophenylcarbamoyloxy)phenyl!-2-2-(N,N-dimethylamino)ethoxy!ethane hydrochloride (compound No. 190).

Production Example 10

(1) 9.5 g of potassium tert-butoxide was added to 92 ml of ethyleneglycol. The mixture was heated to 80° C. Thereto was dropwise added, in3 hours, a solution of 34.7 g of 2-(4-benzyloxyphenyl)oxirane dissolvedin 220 mi of dimethyl sulfoxide. The resulting mixture was stirred for30 minutes at the same temperature. The reaction mixture was cooled andadded to a mixture of 1 liter of ice water and 600 ml of ethyl acetate.The resulting mixture was adjusted to pH 7 with 6N hydrochloric acid.The organic layer was separated. The aqueous layer was extracted with200 ml of ethyl acetate. The extract was combined with the previouslyseparated organic layer. The combined organic layer was washed withwater and a saturated aqueous sodium chloride solution in this order,and dried over anhydrous magnesium sulfate. The solvent was removed bydistillation under reduced pressure. The residue thus obtained waspurified by column chromatography (eluant: chloroform/ethanol=10/1) toobtain 25 g of 1-(4-benzyloxyphenyl)-2-(2-hydroxyethoxy)ethanol.

Melting point: 116.5°-117° C. MeCN!

(2) 22.7 g of 1-(4-benzyloxyphenyl)-2-(2-hydroxyethoxy)ethanol wasdissolved in 140 ml of pyridine. The solution was cooled to -20° C. Tothe solution was added 19 g of p-toluenesulfonyl chloride. The resultingmixture was heated to 0° C. and stirred for 15 hours at the sametemperature. The rection mixture was added to a mixture of 300 ml of icewater and 200 ml of diethyl ether. The resulting mixture was adjusted topH 2 with 6N hydrochloric acid. The organic layer was separated. Theaqueous layer was extracted with 100 ml of diethyl ether. The extractwas combined with the previously separated organic layer. The combinedorganic layer was washed with 1N hydrochloric acid, water and asaturated aqueous sodium chloride solution in this order, and dried overanhydrous magnesium sulfate. The solvent was removed by distillationunder reduced pressure. The residue was purified by columnchromatography (eluant: toluene/ethyl acetate=3/1) to obtain 20.5 g ofoily 1-(4-benzyloxyphenyl)-2- 2-(p-toluenesulfonyl)oxyethoxy!ethanol.

(3) To a mixture of 20 g of 1-(4-benzyloxyphenyl)-2-2-(p-toluenesulfonyloxy)ethoxy!ethanol and 40 ml of methylene chloridecontaining 8.2 g of 3,4-dihydro-2H-pyrane was added 2.3 g of pyridiniump-toluenesulfonate at room temperature. The resulting mixture wasrefluxed for 30 minutes. The reaction mixture was cooled and added to amixture of 100 ml of ice water and 100 ml of methylene chloride. Theorganic layer was separated, washed with water, and dried over anhydrousmagnesium sulfate. The solvent was removed by distillation under reducedpressure to obtain 18.6 g of light yellow oily1-(4-benzyloxyphenyl)-1-(2-tetrahydropyranyloxy)-2-2-(p-toluenesulfonyloxy)ethoxy!ethane.

(4) A mixture of 2 g of1-(4-benzyloxyphenyl)-1-(2-tetrahydropyranyloxy)-2-2-(p-toluenesulfonyloxy)ethoxy!ethane, 5.9 ml of a 40% aqueousmethylamine solution and 20 ml of ethanol was refluxed for 2 hours. Thereaction mixture was cooled and added to a mixture of 50 ml of ice waterand 50 ml of diethyl ether. The organic layer was separated. The aqueuoslayer was extracted twice each with 20 ml of diethyl ether. The extractswere combined with the previously separated organic layer. The combinedorganic layer was mixed with 10 ml of water. The mixture was adjusted topH 1.0 with 6N hydrochloric acid. The aqueous layer was separated andstirred for 30 minutes at room temperature. Thereto was added 30 ml ofchloroform. The resulting mixture was adjusted to pH 12 with a 5%aqueous sodium hydroxide solution. The organic layer was separated,washed with water and a saturated aqueous sodium chloride solution inthis order, and dried over anhydrous magnesium sulfate. The solvent wasremoved by distillation under reduced pressure. The residue was mixedwith 10 ml of acetone. Hydrogen chloride gas was blown into the mixturewith ice cooling. The resulting crystals were collected by filtration,washed with acetone, and dried to obtain 620 mg of1-(4-benzyloxyphenyl)-2-(2-methylaminoethoxy)ethanol hydrochloride(compound No. 191).

Melting point: 173°-173.5° C. EtOH!

The compounds shown in Table 13 were obtained in the same manner.

In Table 13, R¹, R², R³, R^(4a), R^(4b), R⁶, na and nb each show asubstituent or integer used in the following formula:

                                      TABLE 13                                    __________________________________________________________________________     ##STR272##                                                                   Compound                                          Addition                                                                           Melting                No.   R.sup.1   R.sup.2                                                                         R.sup.3                                                                         R.sup.4a                                                                        R.sup.4b                                                                          R.sup.6             na                                                                              nb                                                                              salt point                  __________________________________________________________________________                                                           (°C.)           192                                                                                  ##STR273##                                                                             H H H H                                                                                  ##STR274##         1 1 HCl  158-158.5  IPA!        193   "         " " " "                                                                                  ##STR275##         " " "    170-170.5  EtOH!       194                                                                                  ##STR276##                                                                             " " " "                                                                                  ##STR277##         " " "    180-181  EtOHAcOEt!                                                           N                      195                                                                                  ##STR278##                                                                             " " " "                                                                                  ##STR279##         " " 2HCl 178-180.5  MeCNEt.s                                                           ub.2 O!                196                                                                                  ##STR280##                                                                             H H H H                                                                                  ##STR281##         1 1 HCl  174.5-175  IPA!        197   "         " " " "                                                                                  ##STR282##         " " 2HCl 212.5-213  MeOH!       198   "         " " " "                                                                                  ##STR283##         " " --   Oily                   199   "         " " " "                                                                                  ##STR284##         " " 2HCl 158.5- 160.5                                                                   EtOH!                 200   "         " " " "                                                                                  ##STR285##         " " --   55-58                  201                                                                                  ##STR286##                                                                             H H H H                                                                                  ##STR287##         1 1 --   36-38                  202   "         " " " "                                                                                  ##STR288##         " " "    Oily                   203   "         " " " "                                                                                  ##STR289##         " " HCl  139-141  IPAAcOEt!     204   "         " " " "                                                                                  ##STR290##         " " "    163-164  EtOHMeCN!     205   "         " " " "                                                                                  ##STR291##         " " --   Oily                   206                                                                                  ##STR292##                                                                             H H H H                                                                                  ##STR293##         1 1 --   Oily                   207   "         " " " "                                                                                  ##STR294##         " " "    "                      208   "         " " " "                                                                                  ##STR295##         " " HCl  148.5-149.5                                                                    IPAAcOEt!             209                                                                                  ##STR296##                                                                             " " " "   "                   " " "    173.5-175.5                                                                    EtOHMe.sub.2 CO!      210   "         " " " "                                                                                  ##STR297##         " " PTS  198-200  EtOHAcOEt!                                                           N                      211                                                                                  ##STR298##                                                                             H H H H                                                                                  ##STR299##         1 1 HCl  161-162.5  IPAAcOEt                                                           !                      .sup.  212*.sup.1                                                                    ##STR300##                                                                             Me                                                                              " " "                                                                                  ##STR301##         " " "    Oily                   .sup.  213*.sup.1                                                                    ##STR302##                                                                             " " " "   "                   " " --   "                      __________________________________________________________________________     Note:                                                                         *.sup.1 : Methoxylation was effected using diazomethaneboron trifluoride      in place of using 3,4dihydro-2H-pyran, to obtain the desired product.    

Production Example 11

A mixture of 500 mg of 2- (imidazol-4-yl)methoxy!-1-phenylethanol, 1.1ml of pyridine, 1.1 ml of triethylamine and 1.1 ml of acetic anhydridewas stirred for 1 hour at 100° C. The reaction mixture was cooled toroom temperature. The solvent was removed by distillation under reducedpressure. To the residue were added 1.1 ml of methyl iodide and 5 ml ofacetonitrile. The mixture was allowed to stand at room temperature for24 hours. The solvent was removed by distillation under reducedpressure. To the residue thus obtained were added 4 ml of ethanol and6.8 ml of a 5% aqueous sodium hydroxide solution. The resulting mixturewas stirred at room temperature for 6 hour. The solvent was removed bydistillation under reduced pressure. To the residue thus obtained wereadded 30 ml of chloroform and 20 ml of water. The organic layer wasseparatd, washed with water, and dried over anhydrous magnesium sulfate.The solvent was removed by distillation under reduced pressure. Theresulting oily product was purified by column chromatography (eluant:chloroform/ethanol=10/1). Diisopropyl ether was added to the resultingwhite crystals, and the resulting mixture was filtered to obtain 450 mgof 2- (1-methylimidazol-5-yl)methoxy!-1-phenylethanol (compound No.214).

Melting point: 102°-105° C.

The following compound was obtained in the same manner.

1-(4-Benzyloxyphenyl)-2- (1-methylimidazol-5-yl)-methoxy!ethanol(compound No. 215)

Melting point: 148.5°-150.5° C. IPA-AcOEt!

Production Example 12

1.23 g of N,N'-dicyclohexylcarbodiimide was added, with ice cooling, toa solution of 1.08 g of 2-(2-aminoethoxy)-1-phenylethanol, 730 mg ofnicotinic acid, 810 mg of 1-hydroxybenzotriazole and 0.83 ml oftriethylamine dissolved in 5 ml of tetrahydrofuran. The resultingmixture was stirred at the same temperature for 5 minutes and further atroom temperature for 1 hour. To the reaction mixture was added 11 ml ofethyl acetate. The insolubles were removed by filtration. To thefiltrate was added 5 ml of water and the mixture was adjusted to pH 2with 6N hydrochloric acid. The aqueous layer was separated. The organiclayer was extracted with 5 ml of water. The extract was combined withthe previously separated aqueous layer. The combined aqueous layer wasmixed with 20 ml of chloroform and adjusted to pH 10 with potassiumcarbonate. The organic layer was separated, washed with water, and driedover anhydrous magnesium sulfate. The solvent was removed bydistillation under reduced pressure. The residue thus obtained waspurified by column chromatography (eluant: chloroform/ethanol=15/1) toobtain 400 mg of oily 2-(2-nicotinoylaminoethoxy)-1-phenylethanol(compound No. 216).

IR (neat) cm ⁻¹ : ν_(c=o) 1635

Production Example 13

(1) 5 g of (S)-4-benzyl-2-acetoxymethylmorpholine was dissolved in 10 mlof ethanol. To the solution was added a solution of 1 g of sodiumhydroxide dissolved in 5 ml of water with ice cooling. The mixture wasstirred at room temperature for 10 minutes. The reaction mixture wasadded to 50 ml of ice water and extracted with 50 ml of chloroform. Theorganic layer was washed with water and a saturated aqueous sodiumchloride solution in this order, and dried over anhydrous magnesiumsulfate. The solvent was removed by distillation under reduced pressure.The residue thus obtained was purified by column chromatography (eluant:chloroform/ethanol=30/1) to obtain 3.6 g of oily(S)-4-benzyl-2-hydroxymethyimorpholine.

(2) 3.5 g of (S)-4-benzyl-2-hydroxymethylmorpholine was dissolved in 5ml of ethanol. To the solution was added 5 ml of a 5.9N dry hydrogenchloride-ethanol solution with ice cooling. The resulting mixture wasstirred for 10 minutes at the same temperature. Thereto was added amixture of 500 mg of 5% palladium-carbon and 10 ml of methanol. Theresulting mixture was subjected to hydrogenation for 3 hours at 40° C.After the completion of the reaction, palladium-carbon was removed byfiltration. The solvent was removed by distillation under reducedpressure to obtain a yellow oily product. To the oily product were added20 ml of dry methylene chloride and 4.7 ml of triethylamine. Theresulting mixture was stirred at room temperature for 30 minutes.Thereto was dropwise added a solution of 4.7 g of trityl chloridedissolved in 10 ml of methylene chloride in 20 minutes, with icecooling. The mixture was stirred at room temperature for 3 hours andadded to 50 ml of ice water. The organic layer was separated and 20 mlof water was added thereto. The resulting mixture was adjusted to pH 12with a 1N aqueous sodium hydroxide solution. The organic layer wasseparated and dried over anhydrous magnesium sulfate. The solvent wasremoved by distillation under reduced pressure to obtain a yellow oilyproduct. The oily product was mixed with 10 ml of diisopropyl ether. Theresulting crystals were collected by filtration to obtain 2.7 g of(S)-4-trityl-2-hydroxymethylmorpholine.

Melting point: 142.0°-142.5° C. AcOEt-IPE!

Optical rotation: α!_(D) ²⁷ =-10.9° (C=1, CHCl₃)

The (2R)-form having the following properties was obtained in the samemanner.

Melting point: 142.0°-142.5° C. AcOEt-IPE!

Optical rotation: α!_(D) ²⁷ =+10.9° (C=1, CHCl₃)

(3) The same procedure as in (1) of Production Example 5 was repeated,except that the styrene oxide and the 4-benzyl-2-hydroxymethylmorpholinewere replaced by (S)-2-phenyloxirane and(S)-4-trityl-2-hydroxymethylmorpholine, respectively, to obtain oily(1S,2'S)-1-phenyl-2- (4-tritylmorpholin-2-yl)methoxy!ethanol (compoundNo. 217).

(4) In 20 ml of acetone was dissolved (1S,2'S)-1-phenyl-2-(4-tritylmorpholin-2-yl)methoxy!ethanol. To the solution was added, withice cooling, 7 ml of a 5.9N dry hydrogen chloride-ethanol solution. Theresulting mixture was stirred for 30 minutes at room temperature toeffect a reaction. After the completion of the reaction, the solvent wasremoved by distillation under reduced pressure. The residue thusobtained was added to a mixture of 30 ml of ice water and 30 ml of ethylacetate. The aqueous layer was separated and washed with 30 ml of ethylacetate, after which 50 ml of chloroform was added thereto. Theresulting mixture was adjusted to pH 11 with a 2N aqueous sodiumhydroxide solution. The organic layer was separated, washed with asaturated aqueous sodium chloride solution, and dried over anhydrousmagnesium sulfate. The solvent was removed by distillation under reducedpressure to obtain 1.9 g of a yellow oily product. The oily product wasdissolved in 10 ml of ethanol. To the solution was added 720 mg ofoxalic acid. The resulting mixture was heated to obtain a solution. Thesolution was allowed to stand overnight at room temperature. Theresulting crystals were collected by filtration and dried to obtain 1.8g of (1S,2'S)-1-phenyl-2- (morpholin-2-yl)methoxy!ethanol oxalate(compound No. 218).

Melting point: 130°-132° C. EtOH!

Optical rotation: α!_(D) ²⁴ =+19.9° (C=1, CHCl₃)

The following compounds were obtained in the same manner.

(1R,2'S)-1-phenyl-2- (morpholin-2-yl)methoxy!ethanol maleate (compoundNo. 219)

Melting point: 136°-136.5° C. EtOH!

Optical rotation: α!_(D) ²⁵ =-21.7° (C=1, CH₃ OH)

(1S,2'R)-1-phenyl-2- (morpholin-2-yl)methoxy!ethanol maleate (compoundNo. 220)

Melting point: 136°-136.5° C. EtOH!

Optical rotation: α!_(D) ²⁵ =+22.2° (C=1, CH₃ OH)

(1R,2'R)-1-phenyl-2- (morpholin-2-yl)methoxy!ethanol oxalate (compoundNo. 221)

Melting point: 131°-132.5° C. EtOH!

Optical rotation: α!_(D) ²⁵ =-20.4° (C=1, CH₃ OH)

Production Example 14

(1) 1.19 g of 4-benzylthiobenzaldehyde was dissolved in 20 ml oftetrahydrofuran. The solution was cooled to -10° C. Thereto was dropwiseadded 10 ml of a tetrahydrofuran solution containing 2M of2-chloroethoxymethylmagnesium chloride in 10 minutes. The resultingmixture was stirred for 1 hour with ice cooling. The reaction mixturewas added to a mixture of 50 ml of ice water, 50 ml of ethyl acetate and1 g of ammonium chloride. The resulting mixture was adjusted to pH 2with 6N hydrochloric acid. The organic layer was separated, washed withwater and a saturated aqueous sodium chloride solution in this order,and dried over anhydrous magnesium sulfate. The solvent was removed bydistillation under reduced pressure. The residue thus obtained waspurified by column chromatography eluant: toluene/ethyl acetate=20/1! toobtain 1.34 g of 1-(4-benzylthiophenyl)-2-(2-chloroethoxy)ethanol.

Melting point: 49.5°-50.5° C. hexane-IPE!

(2) A mixture of 600 mg of1-(4-benzylthiophenyl)-2-(2-chloroethoxy)ethanol, 4 ml of a 50% aqueousdimethylamine solution, 310 mg of potassium iodide and 5 ml of ethanolwas refluxed for 4 hours. To the reaction mixture was further added 4 mlof a 50% aqueous dimethylamine solution. The resulting mixture wasrefluxed for 4 hours. The reaction mixture was cooled to roomtemperature. The solvent was removed by distillation under reducedpressure. To the residue thus obtained were added 30 ml of ethyl acetateand 30 ml of water. The resulting mixture was adjusted to pH 10.5 withpotassium carbonate. The organic layer was separated, washed with waterand a saturated aqueous sodium chloride solution in this order, anddried over anhydrous magnesium sulfate. The solvent was removed bydistillation under reduced pressure. The residue was dissolved in 15 mlof acetone. To the solution was added 0.4 ml of a 5N dry hydrogenchloride-ethanol solution. The resulting crystals were collected byfiltration to obtain 590 mg of 1-(4-benzylthiophenyl)-2-2-(N,N-dimethylamino)ethoxy!ethanol hydrochloride (compound No. 222).

Melting point: 173.5°-174.5° C. EtOH!

The compounds shown in Table 14 were obtained in the same manner.

In Table 14, R¹, R², R³, R^(4a), R^(4b), R⁶, na and nb each show asubstitutent or integer used in the following formula:

                                      TABLE 14                                    __________________________________________________________________________     ##STR303##                                                                   Compound                                Addition                                                                           Melting                          No.   R.sup.1        R.sup.2                                                                         R.sup.3                                                                         R.sup.4a                                                                        R.sup.4b                                                                         R.sup.6                                                                             na                                                                              nb                                                                              salt point (°C.)               __________________________________________________________________________    223                                                                                  ##STR304##    H H H H                                                                                 ##STR305##                                                                         1 1 HCl  194-195  EtOH!                   224                                                                                  ##STR306##    " " " "  "     " " "    207-208  EtOHAcOEt!              225                                                                                  ##STR307##    " " " "  "     " " Maleic acid                                                                        168-170 (decomp.)                226                                                                                  ##STR308##    " " " "  "     " " HCl  159.5-160.5  EtOHAcOEt!          227                                                                                  ##STR309##    " " " "  "     " " "    141-142  EtOHAcOEt!              __________________________________________________________________________

Production Example 15

A mixture of 13.2 g of potassium tert-butoxide and 47.2 ml of2-(N,N-dimethylamino)ethanol was heated to 80° C. Thereto was dropwiseadded 40.0 g of 2-(1-naphthyl)oxirane in 3.5 hours. The resultingmixture was stirred for 1.5 hours at 80°-85° C. The reaction mixture wascooled and added to a mixture of 100 ml of ethyl acetate and 100 ml ofice water. The resulting mixture was adjusted to pH 11.5 with 6Nhydrochloric acid. The organic layer was separated. The aqueous layerwas extracted with 50 ml of ethyl acetate. The extract was combined withthe previously separated organic layer. The combined organic layer waswashed with water and a saturated aqueous sodium chloride solution inthis order, and dried over anhydrous magnesium sulfate. The solvent wasremoved by distillation under reduced pressure. The residue thusobtained was subjected to distillation to obtain a fraction having aboiling point of 152°-163° C./0.6-0.8 mm Hg. The oily product obtainedwas dissolved in 200 ml of acetone. Into the solution was blown hydrogenchloride gas with ice cooling. The resulting crystals were collected byfiltraiton, washed with acetone, and dried to obtain 22.7 g of 2-2-(N,N-dimethylamino)ethoxy!-1-(1-naphthyl)ethanol hydrochloride(compound No. 228).

Melting point: 196°-197° C. EtOH!

The compounds shown in Table 15 were obtained in the same manner.

In Table 15, R¹, R², R³, R^(4a), R^(4b), R⁶, na and nb each show asubstituent or integer used in the following formula:

                                      TABLE 15                                    __________________________________________________________________________     ##STR310##                                                                   Compound                                     Addition                                                                           Melting                     No.   R.sup.1        R.sup.2                                                                         R.sup.3                                                                         R.sup.4a                                                                        R.sup.4b                                                                         R.sup.6    na                                                                              nb                                                                              salt point                       __________________________________________________________________________                                                      (°C.)                229                                                                                  ##STR311##    H H H H                                                                                 ##STR312##                                                                              1 1 HCl  193-194  EtOH!              230                                                                                  ##STR313##    " " " "  "          " " "    149-150  Me.sub.2                                                             COEtOH!                     231                                                                                  ##STR314##    " " " "  "          " " "    178-179  Me.sub.2                                                             COEtOH!                     232                                                                                  ##STR315##    " " " "  "          " " "    184-185  Me.sub.2                                                             COEtOH!                      233*                                                                                ##STR316##    H H H H                                                                                 ##STR317##                                                                              2 1 --   Oily                         234* "              " " " "  "          " 2 "    "                           235                                                                                  ##STR318##    " " " "  "          1 1 HCl  213-214  IPA!               236                                                                                  ##STR319##    " " " "  "          " " "    205-205.5  MeOHEtOH!        237                                                                                  ##STR320##    " " " "                                                                                 ##STR321##                                                                              " " "    174-174.5  EtOHEt.sub.2                                                       O!                          238                                                                                  ##STR322##    H H H H                                                                                 ##STR323##                                                                              1 1 HCl  156.6-158  EtOHEt.sub.2                                                       O!                          239                                                                                  ##STR324##    " " " "                                                                                 ##STR325##                                                                              " " "    157-158  IPA!                240*                                                                                ##STR326##    " " " "                                                                                 ##STR327##                                                                              1 1 --   Oily                         241* "              " " " "                                                                                 ##STR328##                                                                              " " "    "                            242* "              " " " "                                                                                 ##STR329##                                                                              " " "    "                           243                                                                                  ##STR330##    H H H H                                                                                 ##STR331##                                                                              1 1 HCl  155.5-157  IPA!             244                                                                                  ##STR332##    " " " "                                                                                 ##STR333##                                                                              " " "    151.5- 153.5  IPA!          245                                                                                  ##STR334##    " " " "  "          " " "    193.5-196.5  EtOH!          246                                                                                  ##STR335##    " " " "  "          " " "    1665.-168  IPA!             247                                                                                  ##STR336##    " " " "  "          " " "    161-163  EtOH!              248                                                                                  ##STR337##    H H H H                                                                                 ##STR338##                                                                              1 1 HCl  100.5- 101.5  IPAAcOEt!                                                       N                           249                                                                                  ##STR339##    " Me                                                                              " "                                                                                 ##STR340##                                                                              " " "    186.5-188  EtOHMe.sub.2                                                       CO!                         250   "              " H Me                                                                              "  "          " " Fumaric acid                                                                       197-198.5  EtOHAcOEt!       251                                                                                  ##STR341##    " " H "  "          " " HCl  199.5-201  IPAAcOEt!        252                                                                                  ##STR342##    " " " "  "          " " "    198-199.5  IPA!             253                                                                                  ##STR343##    H H H H                                                                                 ##STR344##                                                                              1 1 HCl  157-159  IPA!               __________________________________________________________________________     Note:                                                                         *: These compounds were not subject to a step of converting into a            hydrochloride.                                                           

Production Example 16

(1) A mixture of 6.0 g of 2-hydroxymethyl-4-tritylmorpholine, 1.0 g ofpotassium tert-butoxide and 6 ml of dimethyl sulfoxide was heated to 80°C. Thereto was dropwise added, at 80°-85° C. in 2 hours, a solution of2.8 g of 2-(2-naphthyl)oxirane dissolved in 6 ml of dimethyl sulfoxide.The resulting mixture was stirred at the same temperature for 3 hours.The reaction mixture was cooled and added to a mixture of 60 ml of icewater and 60 ml of ethyl acetate. The organic layer was separated,washed with water and a saturated aqueous sodium chloride solution inthis order, and dried over anhydrous magnesium sulfate. The solvent wasremoved by distillation under reduced pressure to obtain 9.0 g of oily1-(2-naphthyl)-2- (4-tritytmorpholin-2-yl)methoxy!ethanol (compound No.254).

In the same manner, there was obtained oily 1-(1-naphthyl)-2-(4-tritylmorpholin-2-yl)methoxy!-ethanol (compound No. 255).

(2) In 50 ml of acetone was dissolved 9.0 g of 1-(2-naphthyl)-2-(4-tritylmorpholin-2-yl)methoxy!-ethanol. To the solution was added 3.5ml of a 5.9N dry hydrogen chloride-ethanol solution with ice cooling.The mixture was stirred for 2 hours at room temperature to effectreaction. After the completion of the reaction, the solvent was removedby distillation under reduced pressure. To the residue thus obtainedwere added 50 ml of water and 30 ml of ethyl acetate. The aqueous layerwas separated and washed with 30 ml of ethyl acetate. Thereto was added50 ml of ethyl acetate. The resulting mixture was adjusted to pH 10.5with potassium carbonate. The organic layer was separated, washed with asaturated aqueous sodium chloride solution, and dried over anhydrousmagnesium sulfate. The solvent was removed by distillation under reducedpressure. The residue thus obtained was purified by columnchromatography (eluant: chloroform/methanol=5/1) to obtain 1.2 g of anoily product. The oily product was dissolved in 5 ml of isopropanol. Tothe solution was added 0.5 g of fumaric acid. The mixture was heated toobtain a solution. The solution was allowed to stand at room temperatureovernight. The resulting crystals were collected by filtration to obtain0.9 g of 1-(2-naphthyl)-2- (morpholin-2-yl)methoxy!ethanol 1/2 fumarate(compound No. 256).

Melting point: 141°-144° C. EtOH!

In the same manner, there was obtained amorphous 1-(1-naphthyl)-2-(mropholin-2-yl)methoxy!ethanol hydrochloride (compound No. 257).

Production Example 17

(1) A mixture of 4.5 g of potassium tert-butoxide and 45 ml of ethyleneglycol was heated to 80° C. Thereto was dropwise added 13.7 g of2-(1-naphthyl)oxirane in 1 hour. The resulting mixture was stirred for 1hour at the same temperature. The reaction mixture was cooled and addedto a mixture of 50 ml of ethyl acetate and 50 ml of ice water. Theorganic layer was separated. The aqueous layer was extracted twice eachwith 20 ml of ethyl acetate. The extracts were combined with thepreviously separated organic layer. The combined organic layer waswashed with water and a saturated aqueous sodium chloride solution inthis order, and dried over anhydrous magnesium sulfate. The solvent wasremoved by distillation under reduced pressure. The residue thusobtained was purified by column chromatography (eluant: toluene/ethylacetate=1/3) to obtain 8.3 g of2-(2-hydroxyethoxy)-1-(1-naphthyl)ethanol.

Melting point: 91°-92° C. IPE!

In the same manner, there was obtained2-(2-hydroxyethoxy)-1-(2-naphthyl)ethanol.

Melting point: 105°-106° C. AcOEt!

(2) 8.3 g of 2-(2-hydroxyethoxy)-1-(1-naphthyl)ethanol was dissolved in50 ml of pyridine. The solution was cooled to -25° C. Thereto was added6.8 g of p-toluenesulfonyl chloride. The resulting mixture was allowedto stand at 0°-5° C. for 24 hours and further at room temperature for 4hours. The reaction mixture was added to a mixture of 103 ml of 6Nhydrochloric acid, 50 ml of ice water and 100 ml of diethyl ether. Theresulting mixture was adjusted to pH 2.0 with 6N hydrochloric acid. Theorganic layer was separated. The aqueous layer was extracted with 20 mlof diethyl ether. The extract was combined with the previously separatedorganic layer. The combined organic layer was washed with water and asaturated aqueous sodium chloride solution in this order, and dried overanhydrous magnesium sulfate. The solvent was removed by distillationunder reduced pressure. The residue thus obtained was purified by columnchromatography (eluant: toluene/ethyl acetate=10/1) to obtain 6.3 g ofcolorless, oily 1-(1-naphthyl)-2-2-(p-toluenesulfonyloxy)ethoxy!ethanol.

In the same manner, there was obtained colorless, oily 1-(2-naphthyl)-2-2-(p-toluenesulfonyloxy)ethoxy!-ethanol.

(3) 0.82 g of pyridinium p-toluenesulfonate was added to a solution of6.3 g of 1-(1-naphthyl)-2- 2-(p-toluenesulfonyloxy)ethoxy!ethanol and2.97 ml of 3,4-dihydro-2H-pyran dissolved in 63 ml of methylene chlorideat room temperature. The resulting mixture was stirred at the sametemperature for 20 minutes and further at 35°-40° C. for 10 minutes. Thereaction mixture was cooled, washed with water, and dried over anhydrousmagnesium sulfate. The solvent was removed by distillation under reducedpressure. The residue thus obtained was purified by columnchromatography (eluant: toluene/ethyl acetate=10/1) to obtain 7.53 g ofcolorless, oily 1-(1-naphthyl)-t-(tetrahydropyran-2-yloxy)-2-2-(p-toluenesulfonyloxy)ethoxy!ethane.

In the same manner, there was obtained colorless, oily1-(2-naphthyl)-1-(tetrahydropyran-2-yloxy)-2-2-(p-toluenesulfonyloxy)ethoxy!ethane.

(4) A mixture of 7.5 g of 1-(1-naphthyl)-1-(tetrahydropyran-2-yloxy)-2-2-(p-toluenesulfonyloxy)ethoxy!ethane, 2.65 ml of N-methylpiperazine,3.96 g of potassium carbonate and 38 ml of N,N-dimethylformamide wasstirred for 2 hours at 90°-100° C. The reaction mixture was cooled andadded to a mixture of 100 ml of diethyl ether and 100 ml of ice water.The organic layer was separated. The aqueous layer was extracted twiceeach with 25 ml of diethyl ether. The extracts were combined with thepreviously separated organic layer. The combined organic layer waswashed with water and a saturated aqueous sodium chloride solution inthis order, and dried over anhydrous magnesium sulfate. The solvent wasremoved by distillation under reduced pressure. The residue thusobtained was purified by column chromatography (eluant:chloroform/ethanol=10/1) to obtain 3.36 g of colorless, oily 2-2-(4-methylpiperazin-1-yl)ethoxy!-1-(1-naphthyl)-1-(tetrahydropyran-2-yloxy)ethane (compound No. 258).

(5) In 30 ml of acetone was dissolved 3.3 g of 2-2-(4-methylpiperazin-1-yl)ethoxy!-1-(1-naphthyl)-1-(tetrahydropyran-2-yloxy)ethane.To the solution were added 3.46 g of p-toluenesulfonic acid monohydrateand 7 ml of water at room temperature. The resulting mixture was stirredat the same temperature for 30 minutes and further at 40° C. for 1 hour.The reaction mixture was added to a mixture of 60 ml of chloroform and60 ml of ice water. The mixture was adjusted to pH 11 with a 10% aqueoussodium hydroxide solution. The organic layer was separated. The aqueouslayer was extracted with 20 ml of chloroform. The extract was combinedwith the previously separated organic layer. The combined organic layerwas washed with water and dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation under reduced pressure. The residuethus obtained was dissolved in 40 ml of acetone. Hydrogen chloride gaswas blown into the solution with ice cooling. The resulting solution wasstirred at room temperature for 30 minutes. Thereto was added 40 ml ofdiethyl ether. The resulting mixture was stirred at the same temperaturefor 30 minutes. The resulting crystals were collected by filtration,washed with acetone, and dried to obtain 2.35 g of 2-2-(4-methylpiperazin-1-yl)ethoxy!-1-(1-naphthyl)ethanol dihydrochloride(compound No. 259).

Melting point: 230°-231.5° C. MeOH!

Production Example 18

The same procedure as in (4) and (5) of Production Example 17 wasrepeated, except that the N-methylpiperazine was replaced byN-(p-fluorobenzoyl)piperidine, to obtain 2-{2-4-(p-fluorobenzoyl)piperidin-1-yl!ethoxy}-1-(1-naphthyl)ethanolhydrochloride (compound No. 260).

Melting point: 204.5°-205.5° C. MeOH!

Production Example 19

In 20 ml of ethanol was dissolved 2 g of1-(1-naphthyl)-1-(tetrahydropyran-2-yloxy)-2-2-(p-toluenesulfonyloxy)ethoxy!ethane. To the solution was added 6.60 gof a 40% aqueous methylamine solution at room temperature. The mixturewas refluxed for 1 hour. The reaction mixture was cooled and added to amixture of 20 ml of ice water and 50 ml of diethyl ether. The organiclayer was separated. The aqueous layer was extracted with 20 ml ofdiethyl ether. The extract was combined with the previously separatedorganic layer. To the combined organic layer was added 15 ml of waterand the resulting mixture was adjusted to pH 1.5 with 6N hydrochloricacid. The aqueous layer was separated. The organic layer was extractedtwice each with 10 ml of water. The extracts were combined with thepreviously separated aqueous layer. The combined aqueous layer was mixedwith 25 ml of chloroform and adjusted to pH 11 with a 10% aqueous sodiumhydroxide solution. The organic layer was separated. The aqueous layerwas extracted twice each with 10 ml of chloroform. The extracts werecombined with the previously separated organic layer. The combinedorganic layer was dried over anhydrous magnesium sulfate. The solventwas removed by distillation under reduced pressure to obtain 1.27 g ofan oily product. The oily product was dissolved in 10 ml of acetone.Into the solution was blown hydrogen chloride gas with ice cooling.Thereto was added 10 ml of diethyl ether. The resulting crystals werecollected by filtration to obtain 0.72 g of 2-2-(N-methylamino)ethoxy!-1-(1-naphthyl)ethanol hydrochloride (compoundNo. 261).

Melting point: 137.5°-139° C. IPA!

The compounds shown in Table 16 were obtained in the same manner.

In Table 16, R¹, R², R³, R^(4a), R^(4b), R⁶, na and nb each show asubstituent or integer used in the following formula:

                                      TABLE 16                                    __________________________________________________________________________     ##STR345##                                                                   Compound                              Addition                                                                           Melting                            No.   R.sup.1    R.sup.2                                                                         R.sup.3                                                                         R.sup.4a                                                                        R.sup.4b                                                                         R.sup.6 na                                                                              nb                                                                              salt point (°C.)                 __________________________________________________________________________    262                                                                                  ##STR346##                                                                              H H H H                                                                                 ##STR347##                                                                           1 1 HCl  180-181  EtOH!                     263   "          " " " "                                                                                 ##STR348##                                                                           " " --   159.5-162                          264   "          " " " "                                                                                 ##STR349##                                                                           " " 1/2 Maleic acid                                                                    184-185  IPAAcOEt!                 265                                                                                  ##STR350##                                                                              " " " "                                                                                 ##STR351##                                                                           " " HCl  170-171  EtOH!                     266   "          " " " "                                                                                 ##STR352##                                                                           " " "    180.5-181.5  IPAEtOH!              __________________________________________________________________________

Production Example 20

A mixture of 3.5 g of potassium tert-butoxide, 9.4 g ofN-tritylethanolamine and 50 ml of dimethyl sulfoxide was heated to 85°C. Thereto was added 5.3 g of 2-(1-naphthyl)oxirane. The resultingmixture was stirred at the same temperature for 5 minutes. The reactionmixture was cooled and added to a mixture of 100 ml of ethyl acetate and150 ml of ice water. The organic layer was separated. The aqueous layerwas extracted with 50 ml of ethyl acetate. The extract was combined withthe previously separated organic layer. The combined organic layer waswashed with water and a saturated aqueous sodium chloride solution inthis order, and dried over anhydrous magnesium sulfate. The solvent wasremoved by distillation under reduced pressure. To the residue thusobtained were added 80 ml of a 50% aqueous formic acid solution and 40ml of tetrahydrofuran. The resulting mixture was stirred at 50°-60° C.for 1 hour. The reaction mixture was cooled. The solvent was removed bydistillation under reduced pressure. To the residue thus obtained wereadded 60 ml of ethyl acetate and 60 ml of water. The resulting mixturewas adjusted to pH 2 with 6N hydrochloric acid. The aqueous layer wasseparated. The organic layer was extracted twice each with 15 ml ofwater. The extracts were combined with the previously separated aqueouslayer. To the combined aqueous layer was added 100 ml of chloroform andthe resulting mixture was adjusted to pH 10.5 with potassium carbonate.The organic layer was separated, washed with water, and dried overanhydrous magnesium sulfate. The solvent was removed by distillationunder reduced pressure. To the residue thus obtained was added 10 ml ofdiisopropyl ether. The resulting crystals were collected by filtrationand dried to obtain 1.8 g of 2-(2-aminoethoxy)-1-(1-naphthyl)ethanol(compound No. 267).

Melting point: 89.5°-92° C. CHCl₃ -Et₂ O!

Production Example 21

7 ml of water and 7 ml of dioxane were added to 0.7 g of2-(2-aminoethoxy)-1-(1-naphthyl)ethanol to obtain a solution. To thesolution was added 0.32 g of potassium carbonate. The resulting mixturewas heated to 50° C. Thereto was added 0.35 g of 2-chloropyrimidine. Theresulting mixture was refluxed for 3 hours. Thereto were added 0.32 g ofpotassium carbonate and 0.35 g of 2-chloropyrimidine. The resultingmixture was further refluxed for 2.5 hours. The reaction mixture wascooled and added to a mixture of 20 mi of ethyl acetate and 20 ml of icewater. The organic layer was separated. The aqueous layer was extractedwith 10 ml of ethyl acetate. The extract was combined with thepreviously separated organic layer. To the combined organic layer wasadded 15 ml of water and the resulting mixture was adjusted to pH 1.5with 6N hydrochloric acid. The aqueous layer was separated. The organiclayer was extracted with 10 ml of water. The extract was combined withthe previously separated aqueous layer. To the combined aqueous layerwas added 50 ml of methylene chloride and the resulting mixture wasadjusted to pH 10.5 with potassium carbonate. The organic layer wasseparated, washed with water, and dried over anhydrous magnesiumsulfate. The solvent was removed by distillation under reduced pressure.The residue thus obtained was purified by column chromatography (eluant:chloroform/ethanol=20/1) to obtain an oily product. To the oily productwere added 4 ml of ethanol and 0.21 g of maleic acid. The resultingmixture was stirred at room temperature for 1 hour. To the reactionmixture was added 2 ml of diethyl ether. The resulting mixture wasstirred at the same temperature for 1 hour. The resulting crystals werecollected by filtration and dried to obtain 0.53 g of1-(1-naphthyl)-2-{2- (pyrimidin-2-yl)amino!ethoxy}-ethanol maleate(compound No. 268).

Melting point: 101.5°-103° C. EtOH-AcOEt!

Production Example 22

0.62 g of N,N'-dicyclohexylcarbodiimide was added to a mixture of 0.7 gof 2-(2-aminoethoxy)-1-(1-naphthyl)ethanol, 0.37 g of nicotinic acid,0.41 g of 1-hydroxybenzotriazole, 0.42 ml of triethylamine and 4 ml oftetrahydrofuran with ice cooling. The resulting mixture was stirred atthe same temperature for 5 minutes and further at room temperature for 1hour. To the reaction mixture was added 6 ml of ethyl acetate. Theinsolubles were removed by filtration. To the filtrate were added 15 mlof ethyl acetate and 20 ml of water. The resulting mixture was adjustedto pH 2 with 6N hydrochloric acid. The aqueous layer was separated. Theorganic layer was extracted twice each with 10 ml of water. The extractswere combined with the previsously separated aqueous layer. To thecombined aqueous layer was added 30 ml of chloroform and the resultingmixture was adjusted to pH 10.5 with potassium carbonate. The organiclayer was separated, washed with water, and dried over anhydrousmagnesium sulfate. The solvent was removed by distillation under reducedpressure. The residue thus obtained was purified by columnchromatography (eluant: chloroform/ethanol=10/1) to obtain an oilyproduct. The oily product was dissolved in 7 ml of acetone. To thesolution was added 0.43 ml of a 5N dry hydrogen chloride-ethanolsolution. The resulting mixture was stirred at room temperature for 1hour. To the reaction mixture was added 3 ml of diethyl ether. Theresulting mixture was stirred at the same temperature for 1 hour. Theresulting crystals were collected by filtration and dried to obtain 0.67g of 1-(1-naphthyl)-2- 2-(nicotinoylamino)ethoxy!ethanol hydrochloride(compound no. 269).

Melting point: 162.5°-163.5° C. EtOH-AcOEt!

Production Example 23

The same procedure as in (1) of Production Example 16 was repeated,except that the 2-(2-naphthyl)oxirane and the2-hydroxymethyl-4-tritylmorpholine were replaced by2-(1-naphthyl)oxirane and 1,4-diformyl-2-piperazinyl methanol,respectively, to obtain oily 2-(1,4-diformylpiperazin-2-yl)methoxy!-1-(1-naphthyl)ethanol (compound No.270).

The compounds shown in Table 17 were obtained in the same manner.

In Table 17, R¹, R², R³, R⁴, R⁶ and n each show a substituent or integerused in the following general formula:

                                      TABLE 17                                    __________________________________________________________________________     ##STR353##                                                                   Compound                         Melting                                      No.   R.sup.1    R.sup.2                                                                         R.sup.3                                                                         R.sup.4                                                                         R.sup.6 n point (°C.)                           __________________________________________________________________________    271                                                                                  ##STR354##                                                                              H H H                                                                                ##STR355##                                                                           1 98-100  AcOEt!                               272                                                                                  ##STR356##                                                                              " " "                                                                                ##STR357##                                                                           " 83-85  AcOEtIPE!                             273                                                                                  ##STR358##                                                                              " " " "       " 72-73.5  AcOEtIPE!                           __________________________________________________________________________

Production Example 24

In 1.5 ml of methanol was dissolved 250 mg of 2-(1,4-diformylpiperazin-2-yl) methoxy!-1-(1-naphthyl)ethanol. To thesolution was added 1.5 ml of a 5N dry hydrogen chloride-ethanolsolution. The mixture was allowed to stand at room temperatureovernight. The resulting crystals were collected by filtration, washedwith ethanol, and dried to obtain 180 mg of 1-(1-naphthyl)-2-(piperazin-2-yl)methoxy!ethanol dihydrochloride (compound No. 274).

Melting point: 199°-201° C. (decomp.)

Production Example 25

The compound obtained in the same manner as in (1) of Production Example16 was reacted with hydrogen chloride gas in the same manner as in theproduction of the hydrochloride of Production Example 22, to obtain thecompounds shown in Table 18.

In Table 18, R¹, R², R³, R⁴, R⁶ and n each show a substituent or integerused in the following general formula:

                                      TABLE 18                                    __________________________________________________________________________     ##STR359##                                                                   Compound                        Addition                                                                           Melting                                  No.   R.sup.1   R.sup.2                                                                         R.sup.3                                                                         R.sup.4                                                                         R.sup.6 n salt point (°C.)                       __________________________________________________________________________    275                                                                                  ##STR360##                                                                             H H H                                                                                ##STR361##                                                                           1 HCl  162-164  EtOHEt.sub.2 O!                 276   "         " " "                                                                                ##STR362##                                                                           " "    143-146                                  277   "         " " --                                                                               ##STR363##                                                                           0 "    151.5-154  EtOHEt.sub.2 O!               278   "         " " H                                                                                ##STR364##                                                                           1 "    154-156  EtOHIPA!                        __________________________________________________________________________

PRODUCTION EXAMPLE 26

The compounds shown in Table 19 were obtained in the same manner as in(1) and (2) of Production Example 16.

In Table 19, R¹, R², R³, R⁴, R⁶ and n each show a substituent or integerused in the following general formula:

                                      TABLE 19                                    __________________________________________________________________________     ##STR365##                                                                   Compound                            Addition                                                                            Melting                             No.   R.sup.1       R.sup.2                                                                         R.sup.3                                                                         R.sup.4                                                                         R.sup.6 n salt  point (°C.)                  __________________________________________________________________________    279                                                                                  ##STR366##   H H H                                                                                ##STR367##                                                                           1 --    Oily                                280   "             " " " "       " 1/2 Fumaric acid                                                                    167.5-170  EtOH!                    281                                                                                  ##STR368##   " " " "       " --    122-123  Me.sub.2 COAcOEt!          282                                                                                  ##STR369##   " " " "       " --    138-139  Me.sub.2 COAcOEt!          __________________________________________________________________________

PRODUCTION EXAMPLE 27

2-(Imidazol-5-yl)methoxy-l-(1-naphthyl)-ethanol was reacted with methyliodide to obtain oily2-(1-methylimidazol-5-yl)methoxy-1-(1-naphthyl)ethanol (compound No.283).

PRODUCTION EXAMPLE 28

(1) 6.0 g of 6-benzyloxy-2-naphthaldehyde was dissolved in 60 ml oftetrahydrofuran. The solution was cooled to -30° C. Thereto was dropwiseadded, in 10 minutes, 30 ml of a tetrahydrofuran solution containing1.6M of 2-chloroethoxymethylmagnesium chloride. The resulting mixturewas stirred for 1 hour with ice cooling. The reaction mixture was addedto a mixture of 100 ml of ice water, 100 ml of ethyl acetate and 3.6 gof ammonium chloride. The mixture was adjsuted to pH 2 with 6Nhydrochloric acid. The organic layer was separated, washed with waterand a saturated aqueous sodium chloride solution in this order, anddried over anhydrous magnesium chloride. The solvent was removed bydistillation under reduced pressure. The residue thus obtained waspurified by column chromatography (eluant: toluene/ethyl acetate=20/1)to obtain a solid. To the solid was added 10 ml of diisopropyl ether.The resulting mixture was stirred at room temperature for 1 hour. Theresulting crystals were collected by filtration and dried to obtain 4.7g of 1-(6-benzyloxy-2-naphthyl)-2-(2-chloroethoxy)ethanol.

    Melting point: 86°-87.5° C.  IPE!

(2) A mixture of 4.5 g of1-(6-benzyloxy-2-naphthyl)-2-(2-chloroethoxy)ethanol, 1 g of potassiumiodide, 10 ml of a 50% aqueous dimethylamine solution and 20 ml ofethanol was refluxed for 3 hours. To the reaction mixture was added 10ml of a 50% aqueous dimethylamine solution. The resulting mixture wasfurther refluxed for 6 hours. The reaction mixture was cooled andconcentrated to about a half volume under reduced pressure. To theconcentrate were added 100 ml of ethyl acetate and 100 ml of water. Themixture was adjusted to pH 10.5 with potassium carbonate. The organiclayer was separated, washed with water and a saturated aqueous sodiumchloride solution in this order, and dried over anhydrous magnesiumsulfate. The solvent was removed by distillation under reduced pressure.To the residue thus obtained was added 30 ml of diethyl ether. Theresulting crystals were collected by filtration and dried to obtain 3.9g of 1-(6-benzyloxy-2-naphthyl)-2- 2-(N,N-dimethylamino)ethoxy!-ethanol(compound No. 284).

    Melting point: 100°-100.5° C.  EtOH-H.sub.2 O!

1-(6-Benzyloxy-2-naphthyl)-2- 2-(N,N-dimethyl-amino)ethoxy!ethanol wastreated in the same manner as in Production Example 22, to obtain1-(6-benzyloxy-2-naphthyl)-2- 2-(N,N-dimethylamino)ethoxy!ethanolhydrochloride (compound No. 285).

    Melting point: 220°-220.5° C.  EtOH!

PRODUCTION EXAMPLE 29

In 12 ml of pyridine was suspended 3.0 g of1-(6-benzyloxy-2-naphthyl)-2- 2-(N,N-dimethylamino)-ethoxy!ethanol. Tothe suspension was added 1.6 ml of acetic anhydride. The resultingmixture was stirred at room temperature for 24 hours. After thecompletion of the reaction, the solvent was removed by distillationunder reduced pressure. To the residue thus obtained were added 60 ml ofethyl acetate and 60 ml of water. The mixture was adjusted to pH 10.5with potassium carbonate. The organic layer was separated. The aqueouslayer was extracted with 30 ml of ethyl acetate. The extract wascombined with the previously separated organic layer. The combinedorganic layer was washed with water and a saturated aqueous sodiumchloride solution in this order, and dried over anhydrous magnesiumsulfate. The solvent was removed by distillation under reduced pressure.The residue thus obtained was dissolved in 30 ml of acetone. To thesolution was added 1.5 ml of a 5N dry hydrogen chloride-ethanolsolution. The resulting mixture was stirred at room temperature for 1hour. The resulting crystals were collected by filtration and dried toobtain 2.6 g of 1-acetoxy-1-(6-benzyloxy-2-naphthyl)-2-2-(N,N-dimethylamino)ethoxy!ethane hydrochloride (compound No. 286).

    Melting point: 157°-158° C.  MeCN!

PRODUCTION EXAMPLE 30

A mixture of 2.0 g of 1-acetoxy-1-(6-benzyloxy-2-naphthyl)-2-2-(N,N-dimethylamino)ethoxy!-ethane hydrochloride, 0.5 g of 5%palladium-carbon and 40 ml of ethanol was subjected to hydrogenation atroom temperature under atmospheric pressure. After the completion of thereaction, the palladium-carbon was removed by filtration. The solventwas removed by distillation under reduced pressure. Acetone was added tothe residue thus obtained. The resulting crystals were collected byfiltration and dried to obtain 0.76 g of1-acetoxy-1-(6-hydroxy-2-naphthyl)-2- 2-(N,N-dimethylamino)ethoxy!ethanehydrochloride (compound No. 287).

    Melting point: 150.5°-151.5° C.  EtOH!

PRODUCTION EXAMPLE 31

A mixture of 360 mg of 1-acetoxy-1-(6-hydroxy-2-naphthyl)-2-2-(N,N-dimethylamino)ethxoy!ethane hydrochloride, 10 ml of water and 15ml of chloroform was adjusted to pH 9 with a saturated aqueous sodiumhydrogencarbonate solution. The organic layer was separated. The aqueouslayer was extracted twice each with 10 ml of chloroform. The extractswere combined with the previously separated organic layer. The combinedorganic layer was washed with saturated aqueous sodium chloride solutionand dried over anhydrous magnesium sulfate. The solvent was removed bydistillation under reduced pressure. The residue thus obtained wasdissolved in 6 ml of benzene. To the solution was added 0.12 ml of ethylisocyanate. The resulting mixture was stirred for 4 hours at 80° C. Thereaction mixture was cooled. The solvent was removed by distillationunder reduced pressure. The residue thus obtained was purified by columnchromatography (eluant: chloroform/ethanol=20/1) to obtain an oilyproduct. The oily product was treated in the same manner asin-Production Example 22 to obtain, as an amorphous, 150 mg of1-acetoxy-1- 6-(N-ethylcarbamoyl)oxy-2-naphthyl!-2-2-(N,N-dimethylamino)ethoxy!ethane hydrochloride (compound No. 288).

PRODUCTION EXAMPLE 32

2- 2-(N,N-dimethylamino)ethoxy!-1-(8-nitro-1-naphthyl)ethanol wasobtained in the same manner as in (1) and (2) of Production Example 27.This compound was reacted with oxalic acid in the same manner as in (2)of Production Example 16 to obtain 2-2-(N,N-dimethylamino)ethoxy!-1-(8-nitro-1-naphthyl)ethanol oxalate(compound No. 289).

    Melting point: 150°-158.5° C.

PRODUCTION EXAMPLE 33

A mixture of 150 mg of 2-2-(N,N-dimethyl-amino)ethoxy!-1-(8-nitro-1-naphthyl)ethanol oxalate, 150mg of 5% palladium-carbon and 3 ml of methanol was subjected tohydrogenation at room temperature for 30 minutes under atmosphericpressure. After the completion of the reaction, the palladium-carbon wasremoved by filtration. The filtrate was subjected to distillation underreduced pressure to remove the solvent. The residue thus obtained wasadded to a mixture of 30 ml of ice water and 30 ml of chloroform. Themixture was adjusted to pH 11 with a 2N aqueous sodium hydroxidesolution. The organic layer was separated, washed with water and asaturated aqueous sodium chloride solution in this order, and dried overanhydrous magnesium sulfate. The solvent was removed by distillationunder reduced pressure. The residue thus obtained was dissolved in 1 mlof ethanol. Thereto was added 0.2 ml of a 5.9N dry hydrogenchloride-ethanol solution. The resulting crystals were collected byfiltration and dried to obtain 110 mg of 1-(8-amino-1-naphthyl)-2-2-(N,N-dimethylamino)ethoxy!ethanol dihydrochloride (compound No. 290).

    Melting point: 195°-198° C. (decomp.)  AcOEt-EtOH!

PRODUCTION EXAMPLE 34

Triethylamine was added to 1-(8-amino-1-naphthyl)-2-2-(N,N-dimethylamino)ethoxy!ethanol hydrochloride. The resulting mixturewas reacted with methanesulfonyl chloride to obtain oily 2-2-(N,N-dimethylamino)ethoxy!-1-(8-methylsulfonylamino-1-naphthyl)ethanolhydrochloride (compound No. 291).

PRODUCTION EXAMPLE 35

The same procedure as in (1) and (2) of Production Example 28 wasrepeated, except that the 6-benzyloxy-2-naphthaldehyde was replaced by4-(N,N-dimethylamino)-1-naphthaldehyde, to obtain oily 1-4-(N,N-dimethylamino)-1-naphthyl!-2-2-(N,N-dimethyl-amino)ethoxy!ethanol dihydrochloride (compound No. 292).

PRODUCTION EXAMPLE 36

13 ml of ethanol was added to 1.3 g of 1-4-N,N-dimethylamino)-1-naphthyl!-2- 2-(N,N-dimethylamino)-ethoxy!ethanoldihydrochloride. The resulting mixture was refluxed for 1 hour. Thereaction mixture was cooled. The solvent was removed by distillationunder reduced pressure. To the residue thus obtained was added a mixtureof 20 ml of ethyl acetate and 20 ml of water. The resulting mixture wasadjusted to pH 10 with potassium carbonate. The organic layer wasseparated, washed with a saturated aqueous sodium chloride solution, anddried over anhydrous magnesium sulfate. The solvent was removed bydistillation under reduced pressure to obtain 1.3 g of oily 1-ethoxy-1-4-(N,N-dimethylamino)-1-naphthyl!-2- 2-(N,N-dimethyl-amino)ethoxy!ethane(compound No. 293).

PRODUCTION EXAMPLE 37

(1) 9.6 g of 5-bromo-1-hydroxyindane was dissolved in 100 ml of drymethylene chloride. To the solution were added, at room temperature, 570mg of pyridinium p-toluenesulfonate and 4.5 ml of 3,4-dihydro-2H-pyran.The resulting mxiture was stirred at the same temperature for 3 hours.The reaction mixture was added to ice water. The organic layer wasseparated, washed with a saturated aqueous sodium chloride solution, anddried over anhydrous magnesium sulfate. The solvent was removed bydistillation under reduced pressure. The residue thus obtained waspurified by column chromatography (eluant: toluene/ethyl acetate=15/1)to obtain 13.1 g of oily 5-bromo-1-(tetrahydropyran-2-yloxy) indane.

(2) 8.1 g of 5-bromo-1-(tetrahydropyran-2-yloxy)-indane was dissolved in100 ml of anhdyrous tetra-hydrofuran under a nitrogen atmosphere. To thesolution was dropwise added 20 ml of a 1.5N n-butyllithium-hexanesolution at -65° C. in 10 minutes. The resulting mixture was stirred atthe same temperature for 5 minutes. Thereto was added 2.3 ml ofanhydrous N,N-dimethylformamide. The reaction mixture was heated to roomtemperature and added to a mixture of 100 ml of ice water, 100 ml ofdiethyl ether and 2 g of ammonium chloride. The organic layer wasseparated, washed with water and a saturated aqueous sodium chloridesolution in this order, and dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation under reduced pressure. The residuethus obtained was purified by column chromatography (eluant:toluene/ethyl acetate=15/1) to obtain 6.5 g of5-formyl-1-(tetrahydropyran-2-yloxy) indane.

(3) The same procedure as in (1) and (2) of Production Example 28 wasrepeated, except that the 6-benzyloxy-2-naphthaldehyde was replaced by5-formyl-1-(tetrahydropyran-2-yloxy) indane, to obtain oily 2-2-(N,N-dimethylamino)ethoxy!-1-1-(tetrahydropyran-2-yloxy)indan-5-yl!ethanol (compound No. 294).

(4) A mixture of 2.5 g of 2- 2-(N,N-dimethyl-amino)ethoxy!-1-1-(tetrahydropyran-2-yloxy)indan-5-yl!-ethanol, 8 ml of acetic anhydrideand 0.64 ml of pyridine was stirred at room temperature for 1 hour. Thereaction mixture was added to a mixture of 50 ml of ice water and 50 mlof diethyl ether. The organic layer was separated and dried overanhydrous magnesium sulfate. The solvent was removed by distillationunder reduced pressure. The residue thus obtained was purified by columnchromatography (eluant: chloroform/methanol=10/1) to obtain 1.9 g ofoily 1-acetoxy-2- 2-(N,N-dimethylamino)ethoxy!-1-1-(tetrahydropyran-2-yloxy)-indan-5-yl!ethane (compound No. 295).

(5) 1.8 g of 1-acetoxy-2- 2'- (N,N-dimethylamino) -ethoxy!-1-1-(tetrahydropyran-2-yloxy)indan-5-yl!ethane was added to 30 ml of a4:2:1 mixed solution of acetic acid, tetrahydrofuran and water. Theresulting mixture was stirred at 70° C. for 2 hours. The reactionmixture was cooled and added to a mixture of 100 ml of water and 100 mlof diethyl ether. The resulting mixture was adjusted to pH 8.5 withpotassium carbonate. The organic layer was separated and dried overanhydrous magnesium sulfate. The solvent was removed by distillationunder reduced pressure. The residue thus obtained was purified by columnchromatography (eluant: chloroform/ethanol=10/1) to obtain 1.0 g of oily1-acetoxy-1- (1-hydroxy) indan-5-yl!-2-2-(N,N-dimethyl-amino)ethoxy!ethane (compound No. 296).

(6) In 5 ml of pyridine was dissolved 1.0 g of 1-acetoxy-1-(1-hydroxy)indan-5-yl!-2- 2-(N,N-dimethylamino)-ethoxy!ethane. To thesolution was added 0.3 ml of methanesulfonyl chloride at roomtemeprature. The resulting mixture was stirred at the same temperatureovernight. The reaction mixture was added to a mixture of 50 ml of icewater and 50 ml of diethyl ether. The resulting mixture was adjusted topH 8.5 with potassium carbonate. The organic layer was separated anddried over anhydrous magnesium sulfate. The solvent was removed bydistillation under reduced pressure. The residue thus obtained waspurified by column chromatography (eluant: chloroform/methanol=10/1) toobtain 80 mg of oily 1-acetoxy-1-(1H-inden-6-yl)-2-2-(N,N-dimethylamino)ethoxy!ethane (compound No. 297).

(7) In 0.5 ml of methanol was dissolved 80 mg oft-acetoxy-1-(1H-inden-6-yl)-2- 2-(N,N-dimethylamino)-ethoxy!ethane. Tothe solution was added 80 mg of a 28% sodium methoxide-methanol solutionwith ice cooling. The resulting mixture was stirred at room temperaturefor 20 minutes. The solvent was removed by distillation under reducedpressure. The residue thus obtained was purified by columnchromatography (eluant: chloroform/methanol=20/1) to obtain a yellowoily product. The oily product was dissolved in 0.1 ml of ethanol. Tothe solution was added 0.1 ml of a 5.9N dry hydrogen chloride-ethanolsolution at room temperature. The resulting crystals were collected byfiltration to obtain 20 mg of 1-(1H-inden-6-yl)-2-2-(N,N-dimethyl-amino) ethoxy!ethanol hydrochloride (compound No. 298).

    Melting point: 168°-171° C. (decomp.)  AcOEt-EtOH!

Note: In the above name of the Compound No. 297 and 298 obtained,respectively, the term "inden-6-yl" was used because it is not clear yetto which carbon of the indene the carbon of the ethoxy group bonds.

PRODUCTION EXAMPLE 38

In the same manner as in the production of hydrochloride in (5) ofProduction Example 37 and Production Example 22, 2-(1-hydroxy)indan-5-yl!-2- 2-(N,N-dimethylamino)ethoxy!ethanolhydrochloride (compound No. 299) was obtained.

    Melting point: 150°-152° C.  IPA!

PRODUCTION EXAMPLE 39

2- 2-(N,N-dimethylamino)ethoxy!-1-(1-naphthyl)ethanol hydrochloride wasreacted with acetic anhydride in pyridine in the presence oftriethylamine to obtain oily 1-acetoxy-2-2-(N,N-dimethyl-amino)ethoxy!-1-(1-naphthyl)ethane (compound No. 300).

PRODUCTION EXAMPLE 40

The compound obtained from 2- 2-(6-methyl-naphthyl)!oxirane in the samemanner as in (1) of Production Example 16 was reacted with hydrogenchloride gas in the same manner as in the production of hydro-chloridein Production Example 22, to obtain oily 2-2-(N-methyl-2,3-dihydropyridin-6H-5-yl)methoxy!-1-2-(6-methylnaphthyl)!ethanol (compound No. 301).

PRODUCTION EXAMPLE 41

The compounds shown in Table 20 were obtained in the same manner as in(1) and (2) of Production Example 28.

In Table 20, R¹, R², R³, R⁴, R⁶ and n each show a substituent or integerused in the following formula:

                                      TABLE 20                                    __________________________________________________________________________     ##STR370##                                                                   Compound                                 Addition                                                                           Melting                         No.   R.sup.1      R.sup.2                                                                         R.sup.3                                                                         R.sup.4                                                                         R.sup.6       n salt point (°C.)              __________________________________________________________________________    302                                                                                  ##STR371##  H H H                                                                                ##STR372##   2 2HCl 237-238 (decomp.)  EtOHH.sub                                                  .2 O!                           303                                                                                  ##STR373##  " " "                                                                                ##STR374##   " HCl  191-191.5  IPA!                 304                                                                                  ##STR375##  " " "                                                                                ##STR376##   " 2HCl 175-176.5 (decomp.)  EtOH!      305   "            " " "                                                                                ##STR377##   " "    122-124  EtOH!                  306                                                                                  ##STR378##  H H H                                                                                ##STR379##   3 --   119-120  AcOEt!                 307   "            " " "                                                                                ##STR380##   " HCl  139-140.5  EtOHAcOEt!           308   "            " " "                                                                                ##STR381##   " "    111.5-112  EtOHAcOEt!           309                                                                                  ##STR382##  " " "                                                                                ##STR383##   2 "    186-187  EtOHAcOEt!             310                                                                                  ##STR384##  H H H                                                                                ##STR385##   2 HCl  160-161.5  EtOHAcOEt!           311                                                                                  ##STR386##  " " " "             " "    149-150  EtOHMe.sub.2           __________________________________________________________________________                                                  CO!                         

PRODUCTION EXAMPLE 42

1.7 g of potassium tert-butoxide was added to 31 ml of2-(N,N-dimethylamino)ethanol. The resulting mixture was heated to 80° C.To the solution was drop-wise added, at 80°-85° C. in 1.5 hours, asolution of 5.2 g of 2-(benzo b!thiophen-5-yl)oxirane dissolved in 8 mlof dimethyl sulfoxide. The resulting mixture was stirred at the sametemperature for 1 hour. The reaction mixture was cooled and added to amixture of 60 ml of ethyl acetate and 60 ml of ice water. The organiclayer was separated. The aqueous layer was extracted with 30 ml of ethylacetate. The extract was combined with the previously separated organiclayer. To the combined organic layer was added 50 ml of ice water andthe resulting mixture was adjusted to pH 1.5 with 6N hydrochloric acid.The aqueous layer was separated and 50 ml of chloroform was addedthereto. The resulting mixture was adjusted to pH 10.5 with potassiumcarbonate. The organic layer was separated, washed with water and driedover anhydrous magnesium sulfate. The solvent was removed bydistillation under reduced pressure. The resulting oily product wasdissolved in 50 ml of acetone. To the solution was added 4.3 ml of a 5Ndry hdyrogen chloride-ethanol solution. The resulting mixture wasstirred at room temperature for 1 hour and 20 ml of diethyl ether wasthen added thereto. The resulting mixture was further stirred for 1hour. The resulting crystals were collected by filtration and dried toobtain 3.3 g of 1-(benzo b!-thiophen-5-yl)-2-2-(N,N-dimethylamino)ethoxy!ethanol hydrochloride (compound No. 312).

    Melting point: 191.5°-192.5° C.  EtOH-Me.sub.2 CO!

The compounds shown in Table 21 were obtained in the same manner.

In Table 21, R¹, R², R³, R⁴, R⁶ and n each show a substituent or integerused in the following formula:

                                      TABLE 21                                    __________________________________________________________________________     ##STR387##                                                                   Compound                          Addition                                                                           Melting                                No.   R.sup.1      R.sup.2                                                                         R.sup.3                                                                         R.sup.4                                                                         R.sup.6                                                                              n salt point (°C.)                     __________________________________________________________________________    313                                                                                  ##STR388##  H H H                                                                                ##STR389##                                                                          2 HCl  139-141                                314                                                                                  ##STR390##  " " " "      " "    165.5-166  EtOHEt.sub.2 O!             315                                                                                  ##STR391##  " " " "      " 2HCl 143-146  EtOH!                         316                                                                                  ##STR392##  " " " "      " HCl  128.5-130  EtOH!                       317                                                                                  ##STR393##  H H H                                                                                ##STR394##                                                                          2 2HCl 185-185.5  EtOHIPA!                    318                                                                                  ##STR395##  " " " "      " HCl  128-130                                319                                                                                  ##STR396##  " " " "      " Fumaric acid                                                                       136-136.5  IPA!                        320                                                                                  ##STR397##  " " " "      " HCl  166.5-167.5 IPAAcOEt!                  321                                                                                  ##STR398##  " " " "      " "    168.5-169.5  IPA!                      322                                                                                  ##STR399##  H H H                                                                                ##STR400##                                                                          2 HCl  169-170                                323                                                                                  ##STR401##  " " " "      " --   Oily                                   324                                                                                  ##STR402##  " " " "      " "    188.5-189  EtOHAcOEt!                  325                                                                                  ##STR403##  " " " "      " "    168-169.5  IPAAcOEt!                   326                                                                                  ##STR404##  " " " "      " "    169-172  EtOH!                         327                                                                                  ##STR405##  H H H                                                                                ##STR406##                                                                          2 HCl  166.5-167.5  EtOHMe.sub.2 CO!          328                                                                                  ##STR407##  " " "                                                                                ##STR408##                                                                          " --   Oily                                    329*                                                                                ##STR409##  " " " "      " 2HCl "                                      330                                                                                  ##STR410##  " " "                                                                                ##STR411##                                                                          " HCl  167.5-169                              331                                                                                  ##STR412##  " " "                                                                                ##STR413##                                                                          " 2HCl Oily                                   332                                                                                  ##STR414##  H H H                                                                                ##STR415##                                                                          2 HCl  207.5-210  EtOH!                       333                                                                                  ##STR416##  " " " "      " "    190.5-192  EtOHIPA!                    334                                                                                  ##STR417##  " " " "      " "    171-172  IPAAcOEt!                     335                                                                                  ##STR418##  " " "                                                                                ##STR419##                                                                          " --   Oily                                   336   "            " " "                                                                                ##STR420##                                                                          3 --   81.5-85                                337                                                                                  ##STR421##  H H H                                                                                ##STR422##                                                                          4 HCl  105-107  EtOHAcOEt!                    338                                                                                  ##STR423##                 Fumaric acid                                                                       123-124.5  EtOHAcOEt!                  __________________________________________________________________________     Note:                                                                         *: This compound can be obtained by subjecting compound No. 328 to            conventional hydrogenation reaction.                                     

PRODUCTION EXAMPLE 43

A mixture of 1.6 g of 3-pyridinemethanol, 1.7 g of potassiumtert-butoxide and 23 ml of dimethyl sulfoxide was heated to 80° C.Thereto was added 2.4 g of 2- (benzo b!furan-5-yl) oxirane. Theresulting mixture was stirred at 85°-90° C. for 15 minutes. The reactionmixture was added to a mixture of 50 ml of ice water and 50 ml of ethylacetate. The resulting mixture was adjusted to pH 1 with 6N hydrochloricacid. The aqueous layer was separated and 30 ml of ethyl acetate wasadded thereto. The resulting mixture was adjusted to pH 9.5 withpotassium carbonate. The organic layer was separated, washed with waterand a saturated aqueous sodium chloride solution in this order, anddried over anhydrous magnesium sulfate. The solvent was removed bydistillation under reduced pressure. The residue thus obtained waspurified by column chromatography (eluant: chloroform/ethanol=50/1) toobtain 0.56 g of 1-(benzo b!furan-5-yl)-2-(pyridin-3-ylmethoxy)-ethanol(compound No. 339).

    Melting point: 85°-86° C.  IPE-EtOH!

The compounds shown in Table 22 were obtained in the same manner.

In Table 22, R¹, R², R³, R⁴, R⁶ and n each show a substituent or integerused in the following formula:

                                      TABLE 22                                    __________________________________________________________________________     ##STR424##                                                                   Compound                             Addition                                                                           Melting                             No.   R.sup.1      R.sup.2                                                                         R.sup.3                                                                         R.sup.4                                                                         R.sup.6   n salt point (°C.)                  __________________________________________________________________________    340                                                                                  ##STR425##  H H H                                                                                ##STR426##                                                                             1 --   106.5-107.5  AcOEtIPE!              341                                                                                  ##STR427##  " " " "         " HCl  Oily                                342                                                                                  ##STR428##  " " "                                                                                ##STR429##                                                                             2 --   "                                   343                                                                                  ##STR430##  H H H                                                                                ##STR431##                                                                             1 --   121.5-125  AcOEt!                   344   "            " " "                                                                                ##STR432##                                                                             " "    127-129.5  EtOHIPE!                 345   "            " " "                                                                                ##STR433##                                                                             " "    95.5-98  AcOEt!                     346   "            " " --                                                                               ##STR434##                                                                             0 HCl  181-185  EtOHAcOEt!                 __________________________________________________________________________

PRODUCTION EXAMPLE 44

(1) A mixture of 5.7 g of potassium tert-butoxide and 57 ml of ethyleneglycol was heated to 80° C. Thereto was added, in 1.5 hours, a solutionof 18 g of 2-(benzo b!thiophen-5-yl)oxirane dissolved in 30 ml ofdimethyl sulfoxide. The resulting mixture was stirred at the sametemperature for 30 minutes. The reaction mixture was added to a mixtureof 120 ml of ice water and 80 ml of ethyl acetate. The organic layer wasseparated. The aqueous layer was extracted twice each with 30 ml ofethyl acetate. The extracts were combined with the previously separatedorganic layer. The combined organic layer was washed with water and asaturated aqueous sodium chloride solution in this order, and dried overanhydrous magnesium sulfate. The solvent was removed by distillationunder reduced pressure. The residue was purified by columnchromatography (eluant: chloroform/ethanol=20/1) to obtain 9.1 g of1-(benzo b!thiophen-5-yl)-2-(2-hydroxyethoxy)-ethanol.

    Melting point: 119°-120.5° C.  EtOH-AcOEt!

(2) In 54 ml of pyridine was dissolved 9.0 g of 1-(benzob!thiophen-5-yl)-2-(2-hydroxyethoxy)ethanol. To the solution was added,at -25° C., 7.2 g of p-toluenesulfonyl chloride. The mixture was allowedto stand at 0°-5° C. for 24 hours and further at room temperature for 4hours. The reaction mixture was added to a mixture of 103 ml of 6Nhydrochloric acid, 50 ml of ice water and 100 ml of diethyl ether. Theresulting mixture was adjusted to pH 2.0 with 6N hydrochloric acid. Theorganic layer was separated. The aqueous layer was extracted with 30 mlof diethyl ether. The extract was combined with the previously separatedorganic layer. The combined organic layer was washed with water and asaturated aqueous sodium chloride solution in this order, and dried overanhydrous magnesium sulfate. The solvent was removed by distillationunder reduced pressure. The residue was purified by columnchromatography (eluant: toluene/ethyl acetate=10/1) to obtain 7.7 g ofcolorless oily 1-(benzo b!thiophen-5-yl)-2-2-(p-toluenesulfonyloxy)ethoxy!ethanol.

(3) 0.97 g of pyridinium p-toluenesulfonate was added, at roomtemperature, to a solution of 7.6 g of 1-(benzo b!thiophen-5-yl)-2-2-(p-toluenesulfonyloxy)-ethoxy!ethanol and 3.5 ml of3,4-dihydro-2H-pyran dissolved in 40 ml of methylene chloride. Themixture was stirred at the same temperature for 20 minutes and furtherat 40-45° C. for 30 minutes. The reaction mixture was washed with waterand dried over anhydrous magnesium sulfate. The solvent was removed bydistillation under reduced pressure to obtain 8.7 g of colorless, oily1-(benzo b!-thiophen-5-yl)-1-(2-tetrahydropyranyloxy)-2-2-(p-toluenesulfonyloxy)ethoxy!ethane.

(4) In 15 ml of ethanol was dissolved 1.5 g of 1-(benzob!thiophen-5-yl)-1-(2-tetrahydropyranyloxy)-2-2-(p-toluenesulfonyloxy)ethoxy!ethane- To the solution was added 4.9 mlof a 40% aqueous methylamine solution. The resulting mixture wasrefluxed for 1 hour. The reaction mixture was added to a mixture of 20ml of ice water and 20 ml of diethyl ether. The organic layer wasseparated. The aqueous layer was extracted with 20 ml of diethyl ether.The extract was combined with the previously separated organic layer. Tothe combined organic layer was added 20 ml of water. The resultingmixture was adjusted to pH 1.5 with 6N hydrochloric acid and stirred atroom temperature for 20 minutes. The aqueous layer was separated. Theorganic layer was extracted with 10 ml of water. The extract wascombined with the previously separated aqueous layer. To the combinedaqueous layer was added 30 ml of methylene chloride. The resultingmixture was adjusted to pH 11 with a 10% aqueous sodium hydroxidesolution. The organic layer was separated. The aqueous layer wasextracted with 15 ml of methylene chloride. The extract was combinedwith the previously separated organic layer and the combined organiclayer was dried over anhydrous magnesium sulfate. The solvent wasremoved by distillation under reduced pressure. The residue thusobtained was dissolved in 7 ml of acetone. To the solution was added 0.5ml of a 5N dry hydrogen chloride-ethanol solution. The resulting mixturewas stirred at room temperature for 1 hour. To the reaction mixture wasadded 7 ml of diethyl ether. The resulting crystals were collected byfiltration to obtain 0.5 g of 1-(benzob!thiophen-5-yl)-2-(N-methylaminoethoxy)ethanol hydrochloride (compoundNo. 347).

    Melting point: 201.5°-202.5° C.  EtOH-Me.sub.2 CO!

The compounds shown in Table 23 were obtained in the same manner.

In Table 23, R¹, R², R³, R⁴, R⁶ and n each show a substituent or integerused in the following formula:

                                      TABLE 23                                    __________________________________________________________________________     ##STR435##                                                                   Compound                                  Addition                                                                           Melting                        No.   R.sup.1    R.sup.2                                                                         R.sup.3                                                                         R.sup.4                                                                         R.sup.6          n salt point (°C.)             __________________________________________________________________________    348                                                                                  ##STR436##                                                                              H H H                                                                                ##STR437##      2 HCl  196.5-197.5  EtOHMe.sub.2                                                     CO!                            349   "          " " "                                                                                ##STR438##      " 2HCl 232-234  MeOHMe.sub.2 CO!      350   "          " " "                                                                                ##STR439##      " HCl  219.5-220  EtOHAcOEt!          351                                                                                  ##STR440##                                                                              H H H                                                                                ##STR441##      2 Oxalic acid                                                                        138-149  EtOHAcOEt!            352   "          " " "                                                                                ##STR442##      " HCl  170.5-171.5  EtOHAcOEt!        353   "          " " "                                                                                ##STR443##      " "    222.5-223  EtOHAcOEt!          __________________________________________________________________________

PRODUCTION EXAMPLE 45

(1) The same procedure as in Production Example 43 was repeated, exceptthat the 2-(benzo b!furan-5-yl)-oxirane and the 3-pyridinemethanol werereplaced by -(benzo b!thiophen-5-yl)oxirane and1,4-diformyl-2-piperazinemethanol, respectively, to obtain oily 1-(benzob!thiophen-5-yl)-2- (1,4-diformylpiperazin-1-yl)methoxy!ethanol(compound No. 354).

(2) In 1.5 ml of methanol was dissolved 270 mg of -(benzob!thiophen-5-yl)-2- (1,4-diformylpiperazin-2-yl)methoxy!ethanol. To thesolution was added 1.5. ml. of a 5N dry hydrogen chloride-ethanolsolution. The resulting mixture was allowed to stand at room temperatureovernight. The resulting crystals were collected by filtration, washedwith ethanol, and dried to obtain 150 mg of 1-(benzo b!thiophen-5-yl)-2-(piperazin-2-yl)methoxy!ethanol dihydrochloride (compound No. 355).

    Melting point: 216°-218° C. (decomp.)

PRODUCTION EXAMPLE 46

(1) A mixture of 10 g of 2-(N-tritylamino)ethanol, 3.7 g of potassiumtert-butoxide and 30 ml of dimethyl sulfoxide was heated to 85° C.Thereto was added a solution of 5.8 g of 2-(benzob!thiophen-5-yl)oxirane dissolved in 10 ml of dimethyl sulfoxide. Theresulting mixture was stirred at the same temperature for 5 minutes. Thereaction mixture was added to a mixture of 150 ml of ice water and 100ml of ethyl acetate. The organic layer was separated. The aqueous layerwas extracted with 30 ml of ethyl acetate. The extract was combined withthe previously separated organic layer. The combined organic layer waswashed with water and a saturated aqueous sodium chloride solution inthis order, and dried over anhydrous magnesium sulfate. The solvent wasremoved by distillation under reduced pressure. To the residue thusobtained were added 70 ml of a 50% aqueous formic acid solution and 30ml of tetrahydrofuran. The resulting mixture was stirred at 50°-60° C.for 1 hours. The solvent was removed by distillation under reducedpressure. To the residue thus obtained were added 50 ml of ethyl acetateand 30 ml of water. The resulting mixture was adjusted to pH 2 with 6Nhydrochloric acid. The aqueous layer was separated. The organic layerwas extracted twice each with 10 ml of water. The extracts were combinedwith the previously separated aqueous layer. To the combined aqueouslayer was added 50 ml of methylene chloride and the resulting mixturewas adjusted to pH 10.5 with potassium carbonate. The organic layer wasseparated, washed with water, and dried over anhydrous magnesiumsulfate. The solvent was removed by distillation under reduced pressureto obtain 1.2 g of 1-(benzo b!thiophen-5-yl)-2-(2-aminoethoxy) ethanol(compound No. 356.

    Melting point: 87°-90.5° C.  EtOH-IPE!

(2) 1.1 g of 1-(benzo b!thiophen-5-yl)-2-(2-aminoethoxy)ethanol wasdissolved in 10 ml of ethanol. To the solution was added 290 mg offumaric acid. The resulting mixture was stirred at room temperature for30 minutes. To the reaction mixture was added 7 ml of diethyl ether. Theresulting mixture was stirred at the same temperature for 1 hour. Theresulting crystals were collected by filtration and dried to obtain 1.2g of 1-(benzo b!thiophen-5-yl)-2-(2-aminoethoxy)ethanol 1/2 fumarate(compound No. 357).

    Melting point: 204.5°-205.5° C.  MeOH-EtOH!

PRODUCTION EXAMPLE 47

The same procedure as in Production Example 46 was repeated, except thatthe 2-(N-tritylamino)-ethanol was replaced by(1-tritylimidazol-4-yl)methanol, to obtain 1-(benzo b!thiophen-5-yl)-2-(imidazolyl)-methoxy!ethanol (compound No. 358) having a melting pointof 128°-129° C. AcOEt!.

In the above name of the compound obtained, the term"(imidazolyl)methoxy" was used because it is not clear yet to whichcarbon of the 4- and 5-position carbons of the imidazolyl group thecarbon of the methoxy group bonds.

PRODUCTION EXAMPLE 48

0.46 g of 1-(benzo b!thiophen-5-yl)-2-(2-aminoethoxy) ethanol wasdissolved in a mixture of 5 ml of water and 5 ml of dioxane. Thereto wasadded 0.21 g of sodium carbonate. The resulting mixture was heated to50° C. Thereto was added 0.22 g of 2-chloropyrimidine. The resultingmixture was refluxed for 3 hours. The reaction mixture was added to amixture of 30 ml of ice water and 30 ml of ethyl acetate. The organiclayer was separated. The aqueous layer was extracted with 10 ml of ethylacetate. The extract was combined with the previously separated organiclayer. To the combined organic layer was added 20 ml of water and theresulting mixture was adjusted to pH 1.5 with 6N hydrochloric acid. Theaqueous layer was separated. The organic layer was extracted with 10 mlof water. The extract was combined with the previously separated aqueouslayer. To the combined aqueous layer was added 50 ml of methylenechloride and the resulting mixture was adjusted to pH 10.5 withpotassium carbonate. The organic layer was separated, washed with water,and dried over anhydrous magnesium sulfate. The solvent was removed bydistillation under reduced pressure. The residue thus obtained waspurified by column chromatography (eluant: chloroform/ethanol=20/1) toobtain an oily product. To the oily product were added 2 ml of ethanoland 70 mg of maleic acid. The resulting mixture was stirred at roomtemperature for 1 hour. To the reaction mixture was added 2 ml ofdiethyl ether. The resulting crystals were collected by filtration anddried to obtain 0.28 g of 1-(benzo b!-thiophen-5-yl)-2-{2-(pyrimidin-2-yl)amino!ethoxy}-ethanol 1/2 maleate (compound No. 359).

    Melting point: 113.5°-14.5° C.  IPA-AcOEt!

PRODUCTION EXAMPLE 49

0.39 g of N,N'-dicyclohexylcarbodiimide was added, with ice cooling, toa mixture of 0.45 g of 1-(benzob!thiophen-5-yl)-2-(2-aminoethoxy)ethanol, 0.23 g of nicotinic acid,0.26 g of 1-hydroxybenzotriazole, 0.26 ml of triethylamine and 3 ml oftetrahydrofuran. The resulting mixture was stirred at the sametemperature for 5 minutes and further at room temperature for 2 hours.To the reaction mixture were added 20 ml of water and 20 ml of ethylacetate. The insolubles were removed by filtration. The filtrate wasadjusted to pH 1.5 with 6N hydrochloric acid. The aqueous layer wasseparated. The organic layer was extracted twice each with 5 ml ofwater. The extracts were combined with the previously separated aqueouslayer. To the combined aqueous layer was added 30 ml of chloroform andthe resulting mixture was adjusted to pH 10.5 with potassium carbonate.The organic layer was separated, washed with water, and dried overanhydrous magnesium sulfate. The solvent was removed by distillationunder reduced pressure. The residue thus obtained. was purified bycolumn chromatography (eluant: chloroform/ethanol=10/1). The resultingoily product was dissolved in 3 ml of ethanol. To the solution was added0.24 ml of a 5N dry hydrogen chloride-ethanol solution. The resultingmixture was stirred at room temperature for 1 hour. To the reactionmixture was added 1.5 ml of diethyl ether. The resulting mixture wasstirred at the same temperature for 1 hour. The resulting crystals werecollected by filtration and dried to obtain 0.31 g of 1-(benzob!thiophen-5-yl)-2- 2-(nicotinoylamino)ethoxy!ethanol hydrochloride(compound No. 360).

    Melting point: 152°-153° C.  EtOH-AcOEt!

PRODUCTION EXAMPLE 50

(1) 1.6 g of 4-methyl-2-formylthiazole was dissolved in 30 ml oftetrahydrofuran. The solution was cooled to -30° C. Thereto was dropwiseadded, in 10 minutes, 10 ml of a tetrahydrofuran solution containing1.6M of 2-chloroethoxymethylmagnesium chloride. The mixture was stirredfor 1 hour with ice cooling. The reaction mixture was added to a mixtureof 50 ml of ice water, 50 ml of ethyl acetate and 2 g of ammoniumchloride. The resulting mixture was adjusted to pH 2 with 6Nhydrochloric acid and stirred at the same temperature for 5 minutes. Thereaction mixture was adjusted to pH 6 with a saturated aqueous sodiumhydrogencarbonate solution. The organic layer was separated, washed withwater and a saturated aqueous sodium chloride solution in this order,and dried over anhydrous magnesium sulfate. The solvent was removed bydistillation under reduced pressure. The residue thus obtained waspurified by column chromatography (eluant: toluene/ethyl acetate=4/1) toobtain 1.3 g of oily 1-(4-methyl-2-thiazolyl)-2-(2-chloroethoxy)ethanol.

(2) A mixture of 1.2 g of1-(4-methyl-2-thiazolyl)-2-(2-chloroethoxy)ethanol, 3 ml of a 50%aqueous dimethylamine solution, 0.45 g of potassium iodide and 20 ml ofethanol was refluxed for 3 hours. To the reaction mixture was added 3 mlof a 50% aqueous dimethylamine solution. The resulting mixture wasrefluxed for 3 hours. The solvent was removed by distillation underreduced pressure. To the residue thus obtained were added 30 ml of ethylacetate and 30 ml of water. The resulting mixture was adjusted to pH 1.5with 6N hydrochloric acid. The aqueous layer was separated and washedwith 10 ml of ethyl acetate. Thereto was added 30 ml of ethyl acetate.The resulting mixture was adjusted to pH 10.5 with potassium carbonate.The organic layer was separated, washed with 10 ml of water and 10 ml ofa saturated aqueous sodium chloride solution in this order, and driedover anhydrous magnesium sulfate. The solvent was removed bydistillation under reduced pressure. The residue thus obtained wasdissolved in 6 ml of ethanol. To the solution were added 0.6 ml of a 5Ndry hydrogen chloride-ethanol solution and 6 ml of diethyl ether. Themixture was stirred at room temperature for 1 hour. The resultingcrystals were collected by filtration, washed with 2 ml of a 1:1 mixtureof diethyl ether and ethanol, and dried to obtain 390 mg of1-(4-methyl-2-thiazolyl)-2- 2-(N,N-dimethylamino)ethoxy!ethanolhydrochloride (compound No. 361).

    Melting point: 159°-160° C.  IPA-AcOEt!

The compounds shown in Table 24 were obtained in the same manner.

In Table 24, R¹, R², R³, R⁴, R⁶ and n each show a substituent or integerused in the following formula:

                                      TABLE 24                                    __________________________________________________________________________     ##STR444##                                                                   Compound                                  Addition                                                                            Melting                       No.   R.sup.1       R.sup.2                                                                         R.sup.3                                                                         R.sup.4                                                                         R.sup.6       n salt  point (°C.)            __________________________________________________________________________    362                                                                                  ##STR445##   H H H                                                                                ##STR446##   2 --    Oily                          .sup.  363*.sup.1                                                                    ##STR447##   " " " "             " 2HCl  185-186.5  EtOHAcOEt!         364                                                                                  ##STR448##   " " " "             " --    Oily                          .sup.  365*.sup.2                                                                    ##STR449##   H H H                                                                                ##STR450##   2 --    Oily                          366                                                                                  ##STR451##   " " " "             " HCl   175-176  EtOHAcOEt!           367                                                                                  ##STR452##   " " " "             " 2HCl  Oily                          368                                                                                  ##STR453##   " " " "             " HCl   182.5-183  EtOHAcOEt!         369                                                                                  ##STR454##   H H H NH.sub.2      2 1/2 Fumaric acid                                                                    170-173                       370                                                                                  ##STR455##   " " "                                                                                ##STR456##   " 2HCl  116-117  EtOHMe.sub.2                                                         CO!                           371                                                                                  ##STR457##   " " " "             " "     179-179.5  EtOHAcOEt!         372                                                                                  ##STR458##   " " " "             " "     155-156  EtOHAcOEt!           373                                                                                  ##STR459##   H H H                                                                                ##STR460##   2 2HCl  184-186  EtOHAcOEt!           374                                                                                  ##STR461##   " " " "             " HCl   196-197  MeOH!                375                                                                                  ##STR462##   " " "                                                                                ##STR463##   " "     193-193.5  EtOHAcOEt!         .sup.  376*.sup.3                                                                    ##STR464##   " " "                                                                                ##STR465##   " "     162-163  IPA!                 377                                                                                  ##STR466##   H H H                                                                                ##STR467##   2 HCl   153,5-154  IPA!               378                                                                                  ##STR468##   " " " "             " 2HCl  176-179                       379                                                                                  ##STR469##   " " "                                                                                ##STR470##   " --    Oily                          380                                                                                  ##STR471##   " " "                                                                                ##STR472##   " "     "                             381                                                                                  ##STR473##   H H H                                                                                ##STR474##   2 HCl   194.5-195  EtOHAcOEt!         382                                                                                  ##STR475##   " " "                                                                                ##STR476##   3 --    109-111  AoOEt!               383   "             " " "                                                                                ##STR477##   " HCl   133.5-134.5  EtOHAcOEt!       384   "             " " "                                                                                ##STR478##   " "     136.5-139.5  EtOHAcOEt!       385                                                                                  ##STR479##   H H H                                                                                ##STR480##   2 HCl   193-193.5  EtOHAcOEt!         386                                                                                  ##STR481##   " " " "             " "     171.5-172  EtOHAcOEt!         387                                                                                  ##STR482##   " " "                                                                                ##STR483##   3 "     137.5-139.5  EtOHAcOEt!       388   "             " " "                                                                                ##STR484##   2 "     138.5-139  EtOHAcOEt!         389                                                                                  ##STR485##   H H H                                                                                ##STR486##   2 HCl   184-184.5  EtOHAcOEt!         390                                                                                  ##STR487##   " " "                                                                                ##STR488##   3 --    68.5-69.5  Hexane!            391                                                                                  ##STR489##   " " "                                                                                ##STR490##   2 2HCl  250-252.5 (decomp.)                                                            MeOHH.sub.2 O!               392   "             " " "                                                                                ##STR491##   " "     155-157  EtOH!                393                                                                                  ##STR492##   H H H                                                                                ##STR493##   3 --    65-67.5  IPAIPE!              394   "             " " "                                                                                ##STR494##   2 2HCl  234-234.5  MeOHAcOEt!         395   "             " " "                                                                                ##STR495##   " HCl   178-180.5  IPAAcOEt!          396                                                                                  ##STR496##   " " "                                                                                ##STR497##   3 --    52-53  IPE!                   397                                                                                  ##STR498##   H H H                                                                                ##STR499##   3 --    81.5-83  IPAIPE!              398   "             " " " "             2 HCl   196-198  EtOHAcOEt!           399   "             " " "                                                                                ##STR500##   " "     190-192.5  EtOHAcOEt!         400                                                                                  ##STR501##   " " "                                                                                ##STR502##   " 1/2 1,5- naphthalene- disulfonic                                               acid Amorphous                     401                                                                                  ##STR503##   Ac                                                                              H H                                                                                ##STR504##   2 HCl   Oily                          402                                                                                  ##STR505##   H " "                                                                                ##STR506##   1 --    "                             403   "             " " "                                                                                ##STR507##   " 1/2 Maleic acid                                                                     110-117                       __________________________________________________________________________     Note:                                                                         *.sup.1 : This compound can be obtained by subjecting compound No. 362 to     hydrolysis reaction using hydrochloric acid.                                  *.sup.2 : This compound can be obtained by subjecting compound No. 364 to     hydrolysis reaction using sodium hydroxide.                                   *.sup.3 : This compound can be obtained by subjecting compound No. 374 to     conventional hydrogenation reaction.                                     

PRODUCTION EXAMPLE 51

(1) A mixture of 9.2 g of 1-(2-thienyl)-2-2-(N,N-dimethylamino)ethoxy!ethanol and 18 ml of acetic anhydride wasrefluxed for 10 minutes. The reaction mixture was dropwise added to amixture of 7.8 ml of concentrated nitric acid and 27 ml of aceticanhydride at 0° C. in 30 minutes. The resulting mixture was stirred atthe same temperature for 2 hours. The reaction mixture was added to asaturated aqueous sodium hydrogen-. carbonate solution with the pH ofthe resulting mixture having been adjusted to 7 with a 40% aqueoussodium hydroxide solution. The resulting mixture was adjusted to pH 10with a 40% aqueous sodium hydroxide solution and 300 ml of chloroformwas added thereto. The organic layer was separated and 300 ml of waterwas added thereto. The resulting mixture was adjusted to pH 2 with 6Nhydrochloric acid. The aqueous layer was separated and 300 ml ofchloroform was added thereto. The resulting mixture was adjusted to pH10 with a 40% aqueous sodium hydroxide solution. The organic layer wasseparated, washed with water, and dried over anhydrous magnesiumsulfate. The solvent was removed by distillation under reduced pressureto obtain 10.4 g of oily 1-(5-nitro-2-thienyl)-1-acetoxy-2-2-(N,N-dimethylamino)ethoxy!ethane (compound No. 404).

(2) In 10 ml of methanol was dissolved 320 mg of1-(5-nitro-2-thienyl)-1-acetoxy-2- 2-(N,N-dimethylamino)-ethoxy!ethane.To the solution was added 1.27 ml of a 1N aqueous sodium hydroxidesolution. The resulting mixture was stirred at room temperature for 1hour. To the reaction mixture were added 40 ml of chloroform and 40 mlof water. The organic layer was separated and 30 ml of water was addedthereto. The resulting mixture was adjusted to pH 2 with 6N hydrochloricacid. The aqueous layer was separated and 30 ml of chloroform was addedthereto. The resulting mixture was adjusted to pH 11 with a 10% aqueoussodium hydroxide solution. The organic layer was separated, washed withwater, and dried over anhydrous magnesium sulfate. The solvent wasremoved by distillation under reduced pressure. To the residue thusobtained were added 3 ml of methanol and 1 ml of a 5N dry hydrogenchloride-ethanol solution. The solvent was removed by distillation underreduced pressure. To the residue thus obtained was added 5 ml ofethanol. The resulting crystals were collected by filtration and driedto obtain 170 mg of 1-(5-nitro-2-thienyl)-2-2-(N,N-dimethylamino)ethoxy!ethanol (compound No. 405).

    Melting point: 189°-191.5° C. (decomp.)

PRODUCTION EXAMPLE 52

(1) In 10 ml of pyridine was dissolved 3.4 g of 2-2-(N,N-dimethylamino)ethoxy!-1-(6-benzyloxybenso b!-furan-2-yl)ethanol.To the solution was added 1.8 ml of acetic anhydride. The resultingmixture was stirred at room temperature for 17.5 hours. The solvent wasremoved by distillation under reduced pressure. To the residue thusobtained were added 40 ml of ethyl acetate and 40 ml of water. Theresulting mixture was adjusted to pH 7 with sodium hydrogencarbonate.The organic layer was separated. The aqueous layer was extracted with 20ml of ethyl acetate. The extract was combined with the previouslyseparated organic layer. The combined organic layer was washed withwater and a saturated aqueous sodium chloride solution in this order,and dried over anhydrous magnesium sulfate. The solvent was removed bydistillation under reduced pressure. The residue thus obtained waspurified by column chromatography (eluant: chloroform/ethanol=1/1) toobtain 3.25 g of oily 1-acetoxy-1-(6-benzyloxybenzo b!furan-2-yl)-2-2-(N,N-dimethylamino)-ethoxy!ethane (compound No. 406).

    IR (neat) cm.sup.-1 : ν.sub.C=O 1740

(2) A mixture of 3.2 g of 1-acetoxy-1-(6-benzyloxybenzo b!furan-2-yl)-2- 2-(N,N-dimethylamino)-ethoxy!ethane, 0.6 g of 5% palladium-carbon,0.67 ml of concentrated hydrochloric acid and 30 ml of methanol wassubjected to hydrogenation at room temperature under atmosphericpressure for 1.5 hours. After the completion of the reaction, thepalladium-carbon was removed by filtration. The solvent was removed bydistillation under reduced pressure. To the residue thus obtained wereadded 20 ml of chloroform and 20 ml of water. The resulting mixture wasadjusted to pH 7 with sodium hydrogencarbonate. The organic layer wasseparated. The aqueous layer was extracted with 10 ml of chloroform. Theextract was combined with the previously separated organic layer. Thecombined organic layer was washed with 5 ml of water, and dried overanhydrous magnesium sulfate. The solvent was removed by distillationunder reduced pressure. The residue thus obtained was purified by columnchromatography (eluant: chloroform/methanol=7/1) to obtain 1.57 g ofoily 1-acetoxy-1-(6-hydroxybenzo b!furan-2-yl)-2-2-(N,N-dimethylamino)ethoxy!ethane (compound No. 407).

    IR (neat) cm.sup.-1 : ν.sub.C=O 1740

(3) In 3.5 ml of benzene was dissolved 0.65 g of1-acetoxy-1-(6-hydroxybenzo b!furan-2-yl)-2-2-(N,N-dimethylamino)ethoxy!ethane. To the solution was added 0.33 ml ofethyl isocyanate. The resulting mixture was stirred for 30 minutes at80° C. The solvent was removed by distillation under reduced pressure.The residue thus obtained was purified by column chromatography (eluant:chloroform/ethanol=6/1) to obtain an oily product. The oily product wastreated with dry hydrogen chloride according to a conventional method toobtain 0.58 g of oily 1-acetoxy-1-(6-N-ethylcarbamoyloxybenzob!furan-2-yl)-2- 2-(N,N-dimethylamino)ethoxy!ethane hydrochloride(compound No. 408).

    IR (neat) cm.sup.-1 : ν.sub.C=O 1730

PRODUCTION EXAMPLE 53

The compounds shown in Table 25 were obtained in the same manner as inProduction Example 50.

In Table 25, R¹, R², R³, R⁴, R⁶ and n each show a substituent or integerused in the following formula:

                                      TABLE 25                                    __________________________________________________________________________     ##STR508##                                                                   Compound                          Addition                                                                           Melting                                No.   R.sup.1      R.sup.2                                                                         R.sup.3                                                                         R.sup.4                                                                         R.sup.6                                                                              n salt point (°C.)                     __________________________________________________________________________    409                                                                                  ##STR509##  H H H                                                                                ##STR510##                                           fumaric acid                   2 1/2                                               162.5˜163  EtOH!                                                  410                                                                            fumaric acid11##  " " " "      " 1/2                                               131˜132.5  EtOH!                                                  411                                                                                  ##STR512##  " " " "      3 --   59.5˜60.5  IPA!                  412                                                                                  ##STR513##  H H H                                                                                ##STR514##                                           fumaric acid                   2 1/2                                               131˜132  EtOH!                                                    413                                                                                  ##STR515##  " " "                                                                                ##STR516##                                                                          " HCl  167˜168                          414   "            " " "                                                                                ##STR517##                                                                          4 "    oily                                   415                                                                                  ##STR518##  " " " "      2 "    152˜153  EtOHAcOEt!              __________________________________________________________________________

PRODUCTION EXAMPLE 54

The compounds shown in Table 26 were obtained in the same manner as inProduction Example 42.

In Table 26

R¹, R², R³, R⁴, R⁶ and n each show a substituent or integer used in thefollowing formula:

                                      TABLE 26                                    __________________________________________________________________________     ##STR519##                                                                   Compound                          Addition                                                                           Melting                                No.   R.sup.1      R.sup.2                                                                         R.sup.3                                                                         R.sup.4                                                                         R.sup.6                                                                              n salt point (°C.)                     __________________________________________________________________________    416                                                                                  ##STR520##  H H H                                                                                ##STR521##                                                                          2 HCl  180˜180.5  EtOHMe.sub.2 CO!      417                                                                                  ##STR522##  " " " "      " "    179˜180                          418                                                                                  ##STR523##  " " "                                                                                ##STR524##                                                                          " "    119.5˜120.5  EtOHAcOEt!          419                                                                                  ##STR525##  H H H                                                                                ##STR526##                                                                          2 HCl  120˜120.5                        420                                                                                  ##STR527##  " " "                                                                                ##STR528##                                                                          " "    175˜176  EtOHAcOEt!              421                                                                                  ##STR529##  " " " "      " "    174˜175.5                        422                                                                                  ##STR530##  " " "                                                                                ##STR531##                                                                          3 "    148.5˜150  EtOHAcOEt!            423                                                                                  ##STR532##  H H H                                                                                ##STR533##                                                                          3 HCl  148.5˜150                        424                                                                                  ##STR534##  " " "                                                                                ##STR535##                                                                          " --   75.5˜76.5  IPA!                  425                                                                                  ##STR536##  " " " "      " "    75.5˜76.5                        426                                                                                  ##STR537##  " " "                                                                                ##STR538##                                                                          " HCl  144˜145.5  IPA!                  427                                                                                  ##STR539##  H H H                                                                                ##STR540##                                                                          3 HCl  144˜145.5                        428                                                                                  ##STR541##  " " "                                                                                ##STR542##                                                                          4 "    151˜152  EtOHAcOEt!              429                                                                                  ##STR543##  " " " "      " "    150.5˜151                        430                                                                                  ##STR544##  " " "                                                                                ##STR545##                                                                          " "    oily                                   431                                                                                  ##STR546##  H H H                                                                                ##STR547##                                                                          4 HCl  oily                                   __________________________________________________________________________     Note:                                                                         *.sup.a : Optical rotation: +48.5° (25° C., C = 1.5, MeOH)      *.sup.b : Optical rotation: +47.8° (25° C., C = 1.5, MeOH)      *.sup.c : Optical rotation: +42.4° (25° C., C = 1.5, MeOH)      *.sup.d : Optical rotation: +47.4° (25° C., C = 1.5, MeOH)      *.sup.e : Optical rotation: +19.1° (25° C., C = 1.5, MeOH)      *.sup.f : Optical rotation: +41.2° (25° C., C = 1.5, MeOH)      *.sup.g : Optical rotation: +32.6° (25° C., C = 1.5, MeOH)      *.sup.h : Optical rotation: +22.9° (25° C., C = 1.5, MeOH) 

Next, this invention is specifically described by way of Examples.However, this invention is in no way restricted to these Examples.

EXAMPLE 1 (TABLETS)

Tablets each containing 50 mg of 1-(4-benzyloxyphenyl)-2-2-(N,N-dimethylamino)ethoxy!ethanol hydrochloride (compound No. 48) wereprepared using the following recipe according to the following method:

    ______________________________________                                        Per tablet:                                                                   ______________________________________                                        Compound No. 48       50 mg                                                   Lactose               20 mg                                                   Kollidon CL (BASF's product)                                                                        15 mg         1                                         Corn starch           30 mg                                                   AVICEL PH 101 (Asahi Kasei's product                                                                50 mg                                                   Polyvinylpyrrolidone K-90                                                                           5 mg                                                     Light silica          3 mg                                                                                       2                                         Magnesium stearate    2 mg                                                    Total                 175 mg                                                  ______________________________________                                    

The components 1 were kneaded with an aqueous solution containing 8% ofPolyvinylpyrrolidone K-90. The kneaded product was dried at 40° C. andmixed with the components 2. The resulting mixture was made into roundtablets each weighing 175 mg and having a diameter of 8 mm.

EXAMPLE 2 (CAPSULES)

Capsules each containing 50 mg of 2- 2-(N,N-dimethylamino) ethoxy!-1- 4-(4-phenyloxy) phenyl!ethanol hydrochloride (compound No. 54) wereprepared using the following recipe according to the following method:

    ______________________________________                                        Per capsule:                                                                  ______________________________________                                        Compound No. 54       50 mg                                                   Lactose               20 mg                                                   Corn starch           53 mg         1                                         Kollidon CL (BASF's product)                                                                        2 mg                                                    Polyvinylpyrrolidone K-90                                                                           5 mg                                                     AVICEL PH 302 (Asahi Kasei's product                                                                18 mg                                                                                      2                                         Magnesium stearate    2 mg                                                    Total                 150 mg                                                  ______________________________________                                    

The components 1 were kneaded with an aqueous solution containing 8% ofPolyvinylpyrrolidone K-90. The kneaded product was dried at 40° C. andmixed with the components 2. The resulting mixture was charged into No.3 gelatin capsules in an amount of 150 mg per capsule to obtaincapsules.

EXAMPLE 3 (LIQUID)

A liquid containing 25 mg of 2-2-(N,N-dimethylamino)ethoxy!-1-(3-trifluoromethylphenyl)ethanolhydrochloride (compound No. 42) was prepared using the following recipeaccording to the following method:

    ______________________________________                                        Per ampule:                                                                   ______________________________________                                        Compound No. 42    25 mg                                                      Methyl paraoxybenzoate                                                                            1 mg                                                      Total              26 mg                                                      ______________________________________                                    

The above components were dissolved in physiological saline and thetotal volume of the solution was made into 1 ml. The solution wasfiltered aseptically and charged into an ampule to obtain a liquid.

EXAMPLE 4 (INJECTION)

An injection containing 25 mg of 2-2-(N,N-dimethylamino)ethoxy!-1-(3-fluorophenyl)ethanol hydrochloride(compound No. 1) was prepared using the following recipe according tothe following method:

    ______________________________________                                               Compound No. 1  25 mg                                                         Manitol         75 mg                                                         Total           100 mg                                                 ______________________________________                                    

The above components were dissolved in 1.5 ml of distilled waterprepared for injection. The solution was filtered aseptically, chargedinto a 3-ml minivial, and freeze-dried to obtain an injection.

EXAMPLE 5 (FINE GRANULES)

Fine granules each containing 50 mg of2-(1-benzylpiperidin-4-yloxy)-1-phenylethanol hydrochloride (compoundNo. 112) were prepared using the following recipe according to thefollowing method:

    ______________________________________                                        Compound No. 112   50 mg                                                      α- Starch    200 mg                                                     Purified sucrose   250 mg          1                                          Lactose            470 mg                                                     Polyvinylpyrrolidone K-90                                                                        30 mg                                                      Total              1000 mg                                                    ______________________________________                                    

The components 1 were subjected to granulation under high speed stirringwith an aqueous solution containing 8% of Polyvinylpyrrolidone K-90. Thegranules obtained were sieved through a 32-mesh screen and dried toobtain fine granules.

EXAMPLE 6 (TABLETS)

2- 2-(N,N-dimethylamino)ethoxy!-1-(3-methylphenyl)ethanol hydrochloride(compound No. 15), 2-(1-methylimidazol-5-yl)methoxy!-1-(4-benzyloxyphenyl)-ethanol (compoundNo. 215), 2- 2-(N,N-dimethylamino)-ethoxy!-1- (1-naphthyl) ethanolhydrochloride (compound No. 228), 2- 2- (N,N-dimethylamino) ethoxy!-1-(2-naphthyl)-ethanol hydrochloride (compound No. 229), 2-2-(N,N-dimethylamino) ethoxy!-1-(benzo b!thiophen-5-yl) ethanolhydrochloride (compound No. 312), 2-(N-methyl-1H-1,2,5,6-tetrahydropyridin-3-yl) methyl!-1- (benzob!-thiophen-5-yl) ethanol (compound No. 345), 2-(2-amino-ethoxy)-1-(benzo !thiophen-5-yl) ethanol 1/2 fumarate (compound No. 357), 2-2-(N,N-diethylamino)ethoxy!-1-(benzo b!thiophen-5-yl) ethanolhydrochloride (compound No. 388) and 2-2-(4-benzylpiperazin-1-yl)ethyl!-1-(benzo b!furan-5-yl) ethanoldihydrochloride (compound No. 394) were processed as in Example 1 toobtain tablets each containing 50 mg of one of the above compounds.

EXAMPLE 7 (CAPSULES)

2- 2-(N,N-dimethylamino)ethoxy!-1-(3-methyl-phenyl)ethanol hydrochloride(compound No. 15), 2- (1-methylimidazol-5-yl) methoxy!-1-(4-benzyloxyphenyl) -ethanol (compound No. 215), 2-2-(N,N-dimethylamino)-ethoxy!-1-(1-naphthyl)ethanol hydrochloride(compound No. 228), 2- 2-(N,N-dimethylamino)ethoxy!-1-(2-naphthyl)ethanol hydrochloride (compound No. 229), 2- 2-(N,N-dimethylamino)ethoxy!-1-(benzo b!thiophen-5-yl)ethanol hydrochloride (compound No.312), 2- (N-methyl-1H-1,2,5,6-tetrahydropyridin-3-yl) methyl!-1-(benzob!thiophen-5-yl)ethanol (compound No. 345), (2-aminoethoxy)-1-(benzob!thiophen-5-yl) ethanol 1/2 fumarate (compound No. 357), 2- 2-(N,N-diethylamino)-ethoxy !-1-(benzo b!thiophen-5-yl) ethanolhydrochloride (compound No. 388) and 2- 2-(4-benzylpiperazin-1-yl)ethyl!-1-(benzo b!furan-5-yl) ethanol dihydrochloride (compound No. 394)were processed as in Example 2 to obtain capsules each containing 50 mgof one of the above compounds.

What is claimed is:
 1. 1-(4-Benzyloxyphenyl)-2-(1-methyl-5-imidazolyl)methoxy!ethanol or a salt thereof.
 2. A method oftreating cerebrovascular dementia, senile dementia, Alzheimer'sdementia, sequelae of ischemic encephalopathy or cerebral apoplexy in apatient, comprising:administration to a patient in need atherapeutically effective amount of a 1,2-ethanediol compound of theformula: ##STR548## wherein R¹ represents a substituted or unsubstitutedphenyl group, the substituent on R¹ being selected from the groupconsisting of a halogen atom, a phenyl-C₁₋₄ alkoxy group, a phenylgroup, a thienyl group, a phenoxy group which may optionally besubstituted by a halogen atom or a lower alkoxy group, and a loweralkoxy group which may optionally be substituted by a thienyl group; R²represents a hydrogen atom; R³ represents a hydrogen atom; nR⁴ 's andnR⁵ 's represent hydrogen atoms; R⁶ represents a 2- or 3-morpholinylgroup, a pyridyl group, an imidazolyl group which may optionally besubstituted by a lower alkyl group, or an amino group which mayoptionally be substituted by a lower alkyl or cycloalkyl group; and nrepresents 0 or an integer of 1 to 6, or a salt thereof.
 3. A method oftreating cerebrovascular dementia, senile dementia, Alzheimer'sdementia, sequelae of ischemic encephalopathy or cerebral apoplexy in apatient, comprising:administration to a patient in need atherapeutically effective amount of 1-(4-benzyloxyphenyl)-2-(1-methyl-5-imidazolyl)methoxy!ethanol or a salt thereof.